WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
per
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 4 :
(11) International Publication Number:
WO 90/02112
C07C 127/19, A23L 1/236
Al
(43) International Publication Date :
8 March 1990 (08.03.90)
(21) International Application Number: PCT/US89/03616
(22) International Filing Date : 22 August 1989 (22.08.89)
(30) Priority data:
235,396
395,242
23 August 1988 (23.08.88)
21 August 1989 (21.08.89)
US
US
(71) Applicant: THE NUTRASWEET COMPANY [US/US];
1751 Lake Cook Road, Box 730, Deerfield, IL 60015
(US).
(72) Inventors : MADIGAN, Darold, L. ; 908 Wisconsin Lane,
Elk Grove Village, IL 60007 (US). MULLER, George,
W. ; 1915 Smith Road, Northbrook, IL 60062 (US).
WALTERS, Eric, D. ; 643 N. Emerald Avenue, Munde-
lein, IL 60060 (US). CULBERSON, John, C. ; 229 S. Sa-
lem Drive, Schaumburg, IL 60193 (US). DUBOIS,
Grant, E. ; 37 Quail Drive, Lake Forest, IL 60045 (US).
CARTER, Jeffery, S. ; 708 Stephan Drive, Palatine, IL
60067 (US). NAGARAJAN, Srivivasan ;
700 W. Rand Road, Arlington Heights, IL 60004 (US). KLIX,
Russel, C ; 4232 Bloomington Avenue, Apt. ,204, Arlington
Heights, IL 60004 (US). AGER, David, J. ; 4700 Arbor Drive,
115, Rolling Meadows, IL 60008 (US). KLADE, Carrie, A. ;
P.O. Box 1539, King of Prussia, PA 19406-0939 (US).
(74) Agent : HOSTER, Jeffrey, M.; 1751 Lake Cook Road,
Deerfield, IL 60015 (US).
(81) Designated States: AU, DK, FI, JP, KR, NO.
Published
With international search report.
(54) Title: SUBSTITUTED ARYL UREAS AS HIGH POTENCY SWEETENERS
(57) Abstract
Substituted ureas and thioureas are disclosed for use as high potency sweeteners.
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
applications under the PCT.
AT
Austria
ES
Spain
MG
Madagascar
AU
Australia
FT
Finland
ML
Mali
BB
Barbados
FR
France
MR
Mauritania
BE
Belgium
GA
Gabon
MW
Malawi
BF
Burkina Fasso
GB
United Kingdom
NL
Netherlands
BG
Bulgaria
HLf
Hungary
NO
Norway
BJ
Benin
rr
Italy
RO
Romania
BR
Brazil
JP
Japan
SD
Sudan
CA
Canada
KP
Democratic People's Republic
SE
Sweden
CF
Central African Republic
of Korea
SN
Senegal
CG
Congo
KR
Republic of Korea
SU
Soviet Union
CH
Switzerland
U
Liechtenstein
TO
Chad
CM
Cameroon
LK
Sri Lanka
TG
Togo
DE
Germany, Federal Republic of
LU
Luxembourg
US
United States of America
DK
Denmark
MC
Monaco
WO 90/02112
PCT/US89/03616
5
10 SUBSTITUTED ARYL UREAS AS HIGH POTENCY SWEETENERS
BACKGROUND OF THE INVENTION
This application is a continuation in part of U.S. Serial No.
15 07/235,396, which is incorporated herein by reference.
The present invention relates to substituted aryl ureas and
thioureas which are useful as sweetening agents. Additionally,
the present invention relates to methods of preparing the novel
compounds, as well as sweetening compositions and food products
20 containing ureas and thioureas as sweeteners.
Certain urea and thiourea derivatives are known in the art as
sweeteners. The commonly known sweetener, suosan, for example,
has the structure CJ
25 H H
Suosan was reported by Petersen and Muller (Chem. Ber. 1948,
81, 31 and Angew, Chem. 1948, 60A, 58). Other examples of urea
and thiourea compounds are found in Z. Lebensm Unters. Forsch.
1982, 175, 266; Japanese Patent 61-260052; Rec. Trav. Chim. 1883,
30 2, 121; Rec. Trav. Chim. 1884, 3, 223; and J. American Chemical
Society 1926, 48, 1069; Naturwissenaschaf ten 1980, 67, 193; and
Naturwissenschaf ten 1981, 68, 143; and U.S. Patent No. 4,645,678
to Nofre et al.
SUMMARY OF THE INVENTION
35 In accordance with the present invention, substituted ureas
are useful as sweetening agents. (For purposes of this
t
WO 90/02112
PCT/US89/03616
-2-
application, the term "urea" includes inventive compounds which
are ureas and thioureas.) The present ureas may be added to food
products in amounts sufficient to sweeten food to a desired
sweetness level.
5 The inventive ureas may be prepared by reacting an isocyanate
or isothiocyanate with an amine or aniline. A wide variety of
ureas may be manufactured by this method.
Particularly desirable urea compounds include:
N-(4-carbamoylphenyl)-N'-[3-(3-phenylpropionic acid)] urea,
10 N-(4-cyanophenyl)-fo'-[3-(3-phenylpropionic acid)] urea,
N-(4-cyanophenyl)'-N'-[3-(3-(3-pyridyl)propionic acid) ] urea,
N-(4-ethoxycarbonylphenyl)-N'-[3-(3-phenylpropionic acid)] urea,
N-(4-ethoxycarbonylphenyl)-N'-[3-(3-(3-pyridyl)propionic acid)]
urea,
15 N-(4-nitrophenyl)-N'-[3-(3-phenylpropionic acid)] urea,
N-(4-nitrophenyl)-N'-[3-(3-(3-pyridyl)propionic acid)] urea, and
N-(4-formylphenyl)-N'-[3-(3-(3-pyridyl)propionic acid)] urea.
N-(4-carbamoylphenyl)-N'-t3-(3-(3-pyridyl)propionic acid)]urea.
N-[5-(2-cyanopyridyl) ]-N'-[3-(3-phenylpropionic acid) ]urea
20 N-t5-(2-cyanopyridyl)]-N'-[3-(3-(3-pyridyl)propionic acid)]urea
N-[5-(2-carbamoylpyridyl)]-N'-[3-(3-phenylpropionic acid) Jurea
N-[5-(2-carbamoylpyridyl)]-N'-[3-(3-(3-pyridyl)propionic
acid) Jurea
N-[5-(2-formylpyridyl) ]-N'-[3-(3-phenylpropionic acid) Jurea
25 N-[5-(2-formylpyridyl) ]-N'-[3-(3-(3-pyridyl)propionic acid) Jurea
Detailed Des cription of the Preferred Embodiment
The present substituted ureas are represented by the
following formula:
30 X, R
II 1 2 \/ 3
R i -N-C-N-C - C - C00H (I)
H H R{ \,
wherein X x is S or 0, wherein R x is an aryl group including
35 optionally substituted cyclic, optionally substituted
heterocyclic including optionally substituted heteroaromatic,
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PCT/US89/03616
10
15
20
25
30
optionally substituted bicyclic including optionally substituted
bicyclic, or optionally substituted phenyl, where the phenyl
corresponds to:
wherein X 2 , X 3 , X 4 , X 5 and X 6 are the same or different and are
selected from the group consisting of:
H,
CF 3 ,
CF 2 CF 3 ,
CF 3 9
C 1 -C 4 alkyl,
CH=N0CH 3 ,
CH=N0H ,
CHO,
CH 2 0CH 3 ,
CH 2 OH ,
CN,
COCF3 ,
COC-f-Cs alkyl,
CONH 2 ,
CONHC 1 -C 3 alkyl,
CONCC^-Ca alkyl) 2 ,
C00C 1 -C 3 alkyl,
COOH,
NH 2 ,
NHCi-03 alkyl,
N(C!-C 3 alkyl) 2 ,
Br,
CI, with the proviso that X 3 and X 5 are not both CI,
F,
I,
NHCHO ,
NHC0CH 3 ,
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PCT/US89/03616
NHC0NH 2 ,
NHS0 2 CH 3 ,
Cj-Cj alkyl C00H,
N0 2 ,
5 OCi-03 alkyl, with the proviso that X 4 is not 0CH 2 CH 3
0C0CH 3 ,
OH,
SCi-03 alkyl,
SOCi-^ alkyl,
10 SO^^ alkyl,
S0 2 NH 2 ,
S0 2 NHC 1 -C 3 alkyl,
S0 2 N(C 1 -C 3 alkyl) 2 ,
SO3H,
15 and where substituents at any two of X 2 , X 3 , X,, Xe or X
form a fused ring,
wherein R 2 , R 3 , R 4 , and R 5 are the same or different and are
selected from the group consisting of
H,
optionally substituted straight chain or branched
C r C 10 alkyl
optionally substituted cyclic C 3 -C 1 0 alkyl,
optionally substituted cyclic,
optionally substituted heterocyclic including
optionally substituted heteroaromatics, optionally
substituted bicyclic including optionally
substituted bicyclic aromatics, or optionally
substituted phenyl, and
enantiomers and physiologically acceptable salts thereof with the
proviso that if X 4 is N0 2 or CN, at least one of the group R 2 ,
R 3 , R 4 , and R 5 is not H, and if one of the group R, , R, , R an d
* 3 ^
R 5 is CH 3 , at least one of the remaining groups is not H.
Suitable heterocyclic moieties for R lt R 2 , R 3 , R 4 , or R
35 include optionally substituted pyridines, thiazoles, indoles,
. naphthyridines, cinnolines, pteridines, thiophenes,
20
25
30
WO 90/02112
PCI7US89/03616
-5-
10
15
20
25
30
benzothiophenes , naphthothiophenes, thianthrenes , furans? pyrans,
isobenzofurans , chromenes, xanthenes, phenoxanthins , pyrroles,
isoindoles, indolizines, pyridazines, pyrimidines, pyrazines,
pyrazoles, imidazoles, pyrroles, indazoles, purines,
quinolizines, isoquinolines , quinolines , phthalazines ,
quinoxalines , quinazolines , carbazoles , carbolines ,
phenanthridines , acridines , pyrimidines , phenanthrolines ,
phenazines , phenarsazines , isothiazoles , pheno thiazines ,
isoxazoles, tetrazoles, triazoles, furazans and heterocyclics of
the following formulas:
vherein R is H or C x -C 6 alkyl. The heterocyclic moieties may be
optionally substituted with one or more substi tuents , such as,
for example, C 1 -C 6 alkyl, halogen, N0 2 , CN, trihalomethyl,
carbamoyl, formyl, dihalomethyl, hydroxyl or hydroxyalkyl .
Preferred R 2 , R 3 , R 4 , or R 5 substituents include
pyridyl and substituted pyridyl
phenyl and substituted phenyl
normal alk(en) (yn)yl C 2 -C 13 ,
branched alk(en) (yn)yl C 3 -C 13 ,
alk(en)yl cycloalk(en)yl C 4 -C 13 ,
cyeloalk(en)yl alk(en)yl C 4 -C 13 ,
alk(en)yl cycloalk(en)yl alk(en)yl C 5 -C x 3
alk(en)yl bicycloalk(en)yl C 7 -C 13 ,
fused bicycloalk(en)yl C 1 ~C 1 5 ,
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10
30
35
alk(en)yl fused bicycloalk(en)yl C 8 -C 13 ,
fused bicycloalk(en)yl alk(en)yl C 8 -C 13 ,
alkenyl fused bicycloalk(en)yl alk(en)yl
fused tricycloalk(en)yl C 10 -C 13 ,
alk(en)yl fused tricycloalk(en)yl C 11 -C 13 ,
fused tricycloalk(en)yl alk(en)yl C 11 -C 13 , or
alk(en)yl fused tricycloalk(en)yl alk(en)yl
^11 "Pi 3
Specifically preferred R 2 , R 3 , R 4 , or R 5 substituents include
CH(CH 3 )C 6 H 5 , alkyl substituted S-phenylethyl, diphenylmethyl,
pyridyl, pyridyl methyl, piperidyl, homopiperidyl, indolyl,
indolinyl, isoindolinyl, quinolyl, isoquinolyl, pyrazinyl,
pyrimidyl, indazolyl, quinoxalinyl, quina^olinyl, purinyl,
15 0CH 2 C 6 H 5 , pyranyl, tetrahydropyranyl, benzofuranyl,
methoxyphenyl , methyloxycarbonylphenyl , 3 , 4-me thylenedi oxy phenyl ,
morpholinyl, benzoxazolyl, acetamidophenyl, cyano, nitro,
thienyl, thienyl methyl, tetrahydro-3-thiophene, benzothienyl,
2,2,4, 4- tetramethyl thiacyclobu t-3-yl , thiazolyl , iso thiazolyl ,
20 S0 2 C 6 H 5 , alkyl substituted -S0 2 C 6 H 5 (S0 2 C 6 H 2 (2,4,6-trimethyl) ,
S0 2 C 6 H 2 (2 , 4 , 6- tr i isopropyl ) ) , S0 2 c-C 6 E 1 x ,
S0 2 c-C 7 H 13 , 6-oxo-cis-hydrindanyl, chlorophenyl,
fluorophenyl, and trif luoromethylphenyl.
25 Particularly preferred are those ureas wherein R 2 is selected
from the group consisting of pyridyl and substituted pyridyl,
benzyl, phenyl and substituted phenyl, benzhydryl, substituted
cycloalky 1 .
Preferably, the inventive urea is one where R x is
NC CH,C0-^Oy C 2 H 5 0 2 C-
°2N-^Q^ CH 3 S0 2 -^Q^
H,NC0CH
CH 3 0 2 C-^Q^~ 2-indanyl H 2 NC0(CH 2 ) 2
WO 90/02112 PCT/US89/03616
-7-
0 0
Cl-( O ) 6-indazolyl H 2 N-S
N i
ncYo\
H,NCO
-<0) NC-^
> N
H 2
ON ON
10 R 2 is phenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl,
4-methoxyphenyl, naphthyl, quinolyl, isoquinolyl or
( CH 2>i-6< c y cl oalkyl),
R 3 , R 4 , and R 5 are H and
X a is 0.
15 There are two isomeric forms (R) and (S) of some preferred
compound- The form having more sweetening potency
is believed to be the (S) isomer, and is preferred
for purposes of this invention.
Particularly preferred compounds include those wherein
20
R A is NC-/o \, R 2 is 3-pyridyl, R 3 , R 4 , and
R 5 arelT, and X x is 0,
r~\
R x is NW O V, R 2 is phenyl, R 3 , R 4 , and R 5
25 are H and ^ is 0,
R x is 0 2 N-/ O V R 2 is 3-pyridyl, R 3 , R 4 , and
R 5 are a and X t is 0,
30 R x is C 2 H 5 0 2 C-/Oy-, R 2 is 3-pyridyl, R 3 ,
R 4 , and R 5 are H and X r is 0 ,
R r is C 2 H 5 0 2 C-^o\-, R 2 is phenyl, R 3 ,
R 4 , and R 5 are H and X x is 0 ,
35
-8-
PCT/US89/03616
R i is H 2 NC0-^2>T R 2 is phenyl, R 3 , R 4 , and R 5 and H and
X x is 0
and R x is 0 2 N-(o}- , R 2 is phenyl, R 3 , R 4 ,
and R 5 are H and X x is 0,
R t is CH0-<g>- , R 2 is 3-pyridyl, R 3 , R 4 , and R 5 are
H and X lt is 0,
0
R x is H 2 NC-(OV , R 2 is 3-pyridyl, R 3 , R 4 , and R ;
are H anST"^ is 0,
R x is NC-<o^_, r 2 is phenyl, R 3 , R 4 , and Rg are H and
X x is 0 ;
R i is NC-(o^- , R 2 is 3-pyridyl, R 3 , R 4 and R 5 are H
and X x is 0
0
R x is H 2 N- C-J^y ,R 2 i s phenyl, R 3 , R 4 and R 5 are
H and X t is 0
0
R x is H 2 N- C-^o)- , R 2 is 3-pyridyl, R 3 , R 4 , and R 5
are H and X x is 0
0
R x is H 2 N- C R 2 is phenyl, R 3 , R 4 , and R 5 are H
and X L is 0
0
Ri is H 2 N- C-<2>T R 2 is 3-pyridyl, R 3 , R 4 , and R 5 are H
and is 0
R i is 0HC -\£_/"" * R 2 is P hen yl» R 3 » R 4 » and R 5 are H
and X L is 0
R x is 0HC^g>- , R 2 is 3-pyridyl, R 3 , R 4 , and R 5 are H
and X 1 is 0
R, is 0HC-£o>-; r 2 is phenyl} Rj f R< ? and ^ are fi ^
X x is 0
4
t
WO 90/02112 PCT/US89/03616
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H and X 1 is 0.
The present ureas also include physiologically acceptable
salts of the compounds described above. The ureas also may have
two asymmetrical carbon atoms, i.e., optically active sites as
asterisked in the following structure:
10
COOH
15 These ureas exist in (R) and (S) enantiomeric forms if there
is one optically active site. If both sites are optically
active, there are four possible diastereomic forms: (R)(R),
<R)(S), <S)(R), and (S)(S).
The present invention also relates to edible products
20 containing the present urea compounds as sweetening agents either
alone or in combination with other sweeteners. Also provided by
the present invention is a process for sweetening edible products
such as foods, beverages, chewing gums, confections,
pharmaceuticals, veterinary preparations and the like.
25 The present invention further contemplates compositions of
the present ureas in combination with other sweetening agents
and/or physiologically acceptable carriers which may be bulking
agents. Suitable carriers include water, polymeric dextrose such
as polydextrose, starch and modified starches, maltodextrins ,
30 cellulose, methylcellulose, maltitol, cellobiitol,
carboxymethylcellulose, hydroxypropylcellulose, hemicelluloses
microcrystalline cellulose, other cellulose derivatives, sodium
alginate, pectins and other gums, lactose, maltose, glucose,
leucine, glycerol, mannitol, sorbitol, sodium bicarbonate and
35 phosphoric, citric, tartaric, fumaric, benzoic, sorbic, propionic
acids and their sodium, potassium and calcium salts and mixtures
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of all of the above.
Suitable sweetening agents which may be used in combination
with the present ureas can be sugars or high potency sweeteners
such as sucrose, corn syrups, fructose, high fructose corn syrup,
5 aspartame, alitame, neohesperidin dihydrochalcone, hydrogenated
isomaltulose (Palatini te) , stevioside type sweeteners, L-sugars,
glycyrrhizin, xylitol, lactitol, neosugar, acesulfam-K, saccharin
(sodium, potassium or calcium salt), cyclamic acid (sodium,
potassium or calcium salt), sucralose, monellin and thaumatin and
10 mixtures thereof, '
The present invention also relates to a novel method of
preparing the inventive urea compounds. An isocyanate of the
formula
R 1 UCX 1
15 with R^ and chosen as desired from the substituents earlier
disclosed is reacted with a substituted beta-amino acid, such as
a beta-alanine of the formula
with R 2 , R 3 , R 4 , and R 5 chosen as desired from the
substituents earlier disclosed. The ester of the g
amino acids may also be used. The substituted
beta-amino acid may be prepared by the methods
disclosed in:
U.S. Patent 4,127,570 to Fosker
30 Journal of the Chemical Society (1936), V.59, p. 299
Journal of the Chemical Society (1929), V.51, p. 41
Liebigs Ann. Chemistry (1981), V.12, p.2258
Synthetic Communication (1981), V.ll, p. 95
Synthesis (1982), p. 967
35 Chem. Pharm. Bull. (1978), 26, 260-263
each of which is incorporated herein by reference.
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PCT/US89/03616
The isocyanate and substituted beta-amino acid may be reacted
in the presence or absence of a base- The reaction is preferably
carried out in the presence of a solvent such as acetoni trile, a
5 mixture of acetoni trile and water, methanol, acetone, or a
mixture of ethyl acetate and water.
Anilines may also be reacted with isocyanates or
isothiocyanates of a substituted (3-amino acid ester followed by
ester hydrolysis.
10 In some of the desired compounds, it is preferable to isolate
one of two enantiomeric forms. An aldehyde and a chiral amine
are reacted to produce a Schiff base. The Schiff base is reacted
with a methyl haloacetate in THF with a metal such as zinc to
produce a diastereomeric mixture of a 3-lactam. The desired
15 diastereomer is separated after the 3-lactam is hydrolyzed and
esterified to produce an ester of a first (3-amino acid. After
hydrogenolysis, the desired stereoisomer of a second (S-amino acid
is obtained.
For some applications, esterif i cation is not necessary. In
20 these applications, the desired diastereomer of the g- lactam is
isolated and then hydrolyzed to produce a diastereomeric mixture
of a first (3-amino acid. The first 0-amino acid is then
hydrogenolyzed to produce the desired stereoisomer of a second
(3-amino acid.
25 The present invention also relates to a method of sweetening
foods or comestible products. In such uses, the present ureas
are added to any consumable product in which it is desired to
have a sweet taste. The inventive urea* compounds are added to
such products in amounts effective to impact the desired level of
30 sweetness. The optimum amount of the urea sweetener agent will
vary depending on a variety of factors, including the sweetness
potency of a particular urea sweetening agent, storage and use
conditions of the product, the particular components of the
product, the flavor profile of the comestible product, and the
35 level of sweetness desired. One skilled in the art can readily
determine the optimum amount of sweetening agent to be employed
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10
in a particular formulation of a food product by conducting .
routine sweetness (sensory) experiments. Usually, the present
sweetening agents are added to the comestible products in amounts
of from about 0-00001 to about 0.1 percent by weight of the
comestible product, advantageously from about 0.00005 to about
0.05 weight percent and preferably from about 0.001 to about 0.02
weight percent. Concentrates, of course, will contain higher
percentages of sweetening agent (s), and are diluted for end use
purposes.
Suitable products which are sweetened by the present
sweetening agents include any products for which a sweet flavor
component- is desired such as food products (for human or animal
consumption), beverages (alcoholic, soft drinks, juices,
carbonated beverages), confectionary products (candies, chewing
15 gum, baked goods, pastries, breads, etc.), hygiene products,
cosmetics, pharmaceutical products and veterinary products. In
sweetening gum, the present ureas can be added in amounts in
excess of a sucrose equivalent normally found in gum. This
excess amount of urea sweetener may provide a longer sweet taste
20 due to its lower solubility compared to sucrose and enhancement
of flavor (flavor enhancer).
The present ureas can be added in pure form to foods to
impart a sweet flavor. However, because of the high sweetness
potency of the present sweetening agents, they are typically
25 admixed with a carrier or bulking agent. Suitable carriers or
bulking agents include water, polymeric dextrose such as
Polydextrose, starch and modified starches, maltodextrins,
cellulose , hemicellulose , me thylcellulose ,
carboxyrae thylcellulose, cellobiitol, hydroxypropylcellulose,
30 hemicelluloses microcrystalline cellulose, cellulose derivatives,
sodium alginate, pectins and other gums, lactose, maltose,
maltitol, glucose, leucine, glycerol, mannitol, sorbitol, sodium
bicarbonate and phosphoric, citric, tartaric, fumaric, benzoic,
sorbic and propionic acids and their sodium, potassium and
35 calcium salts and mixtures of all of the above.
The present ureas can be employed alone as the sole
WO 90/02112
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PCT/US89/03616
sweetening agent in a comestible product. Mixtures of more than
one of the inventive ureas can also be employed* Additionally,
the ureas can be used in combination with other sweetening agents
such as sugars (such as fructose and sucrose), corn syrups, high
5 potency sweeteners such as aspartame and alitame, and other
sweeteners such as glycyrrhizin, aminoacyl sugars, xylitol,
sorbitol, mannitol, acesulfam K, thaumatin, monellin, cyclamates,
saccharin, neohesperidin dihydrochalcone, hydrogenated
isomaltulose, (Palatinit), stevioside type sweeteners, lactitol,
10 neosugar, L-sugars, sucralose, and mixtures thereof.
The compounds synthesized were tasted as aqueous solutions at
1 mg/ml and 10 fold dilutions thereof and compared in taste
quality and intensity to a sucrose standard solution- All
compounds were found to be sweet*
15 The following examples illustrate the practice of the present
invention, but should not be construed as limiting its scope.
EXAMPLES
20 EXAMPLE 1
Preparation of N-(4-Ethoxycarbonylphenyl)-N' -[ 3-(3-
phenylpropionic acid)]urea*
25 To a stirred solution of 4-ethoxy car bony lphenyl isocyanate
(2.16 g, 11.3 mmol) in 35 ml of acetonitrile was added a solution
of 3-amino-3-phenylpropionic acid (1.90 g, 11.5 mmol) and sodium
hydroxide (0.458 g, 11.5 mmol) in a mixture of 6 ml of water and
6 mL of acetonitrile. The reaction mixture was stirred for 16
30 hours, then concentrated. The residue was diluted with water (50
ml) and extracted with methylene chloride (25 mL) and ethyl
acetate (25 ml). The aqueous layer was acidified with 11.5 mL of
1 N HC1 and stirred for 30 minutes. The resulting slurry was
filtered and the solid was washed with copious amounts of water.
35 The solid was dried iji vacuo to afford 3.61 g (90%) of the urea
as white powder. PMR (dmso-D 6 ) S 12.3 (s, 1 H), 9.03 (s, 1 H),
WO 90/02112
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PCT/US89/03616
10
20
30
7.82, 7.50 (abq, 4H) , 7.45-7.2 (m, 5 H), 6.96 (d, 1H, J. 8.4 Hz),
5.14 (overlapping dt, 1H) , 4.24 (q, 2 H, J= 7 Hz), 2.78 (m, 2 H),
1.28 (t, 3 H, J= Hz). CMR (dmso-D 6 ) 5 172.0, 165.5, 153.9,
144.9, 142.6, 130.3, 128.3, 127.0, 126.3, 122.1, 116.7, 60.2,
50.0, 40.9, 14.2 IR(KBr)cm -1 3400, 3340, 3200, 2980, 1710, 1650,
1595, 1553; 1512, 1409. Anal, calcd. for C 19 H 20 N 2 0 5 -0. 17 H 2 0: C,
63.49; H, 5.70; N, 7.79. Found: C, 63.47: H, 5.68: N, 7.63.
EXAMPLE 2
Preparation of N-(4-Acetylphenyl)-N'-[3-(3-phenylpropionic
acid) ]urea.
To a stirred solution of 4-acetylphenyl isocyanate (1.87 g,
15 11.6 mmol) in 35 mL of acetonitrile was added a solution of
3-amino-3-phenylpropionic acid (1.95 g, 11.8 mmol) and sodium
hydroxide (0.472 g, 11.8 mmol) in a mixture of 6 ml of vater and
6 ml of acetonitrile. Solid formed in the reaction material
immediately. The reaction mixture was stirred for 17 hours, then
concentrated. The residue was diluted with water (75 ml) and
extracted with ethyl acetate (2 x 25 mL ea. ) The aqueous layer
was concentrated to remove traces of ethyl acetate. The aqueous
layer was then acidified with 14 ml of 1 N HC1 and the product
gummed out. The resulting suspension was stirred and the gum
25 solidified. The slurry was filtered and the solid was washed
with copious amounts of water. The solid was dried in vacuo to
afford 3.30 g (87%) of the urea as tan powder. The crude product
was recrys tallized from acetonitrile to afford 1.67 g (442) of
the urea. PMR (dmso-D 6 ) S 12.3 (s, 1 H), 9.01 (s, 1 H), 7.81 (d,
2 H, J= 8.8 Hz), 7.47 (d, 2H, J= 8.8 Hz), 7.4-7.15 (m, 5 H), 6.95
(d, 1H, J= 8.4 Hz), 5.11 (apparent q, 1 H), 2.85-2.6 (m, 2 H),
2.45 (s, 3 H). CMR (dmso-D 6 ) 5 196.2, 172.0, 153.9, 144.9,
142.6, 129.6, 128.3, 127.0, 126.3, 116.7, 49.9, 40.9, 26.3.
35
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EXAMPLE 3
Preparation of N-(4-Bromophenyl)-N'-[3-(3-phenylpropionic
acid) jurea.
5
To a stirred solution of 4-bromophenyl isocyanate (2.69 g,
13.6 mmol) in 35 mL of acetonitrile was added a solution of
3-amino-3-phenylpropionic acid (2.29 g, 13.9 mmol) and sodium
hydroxide (0.555 g, 13.9 mmol) in a mixture of 6 ml of water and
10 6 mL of acetonitrile. The reaction mixture was stirred for 24
hours, then concentrated. The residue was diluted with water (75
ml) and extracted with ethyl acetate (2 x 50 ml). The aqueous
layer was concentrated to remove traces of ethyl acetate and then
acidified with 20 mL of 1 N HC1. The resulting thick slurry was
15 diluted with water and filtered. The solid was washed with
copious amounts of water and dried in vacuo to afford 3.61 g
(90%) of the urea as white powder. PMR (dmso-D 6 ) 5 12.3 (bs, 1
H) , 8.73 (s, 1 H), 7.45-7.2 (m, 9H), 6.84 (d, 1H, J= 8.4 Hz),
5.11 (apparent q, 1 H), 2.85-2.65 (m, 2 H). CMR (dmso-D 6 ) S
20 172.0, 154.1, 142.7, 139.7, 131.4, 128.3, 126.9, 126.3, 119.5,
112.4, 49.9, 40.9.
EXAMPLE 4
25 Preparation of N-(4-cyanophenyl)-N'-[3-(3-phenylpropionic
acid) Jurea
To a solution of 1.652 g (11.5 mmol) of 4-cyanophenyl
isocyanate in 50 mL acetonitrile was added 1.893 g (11.5 mmol) of
30 3-amino-3-phenylpropionic acid slurried in 50 ml acetonitrile.
After 1 hour at room temperature the reaction mixture was heated
to reflux where, after the addition of an additional 50 ml of
acetonitrile, a clear solution formed. The reaction mixture was
cooled with stirring overnight. The solids were filtered off and
35 dried at 40° C/l mm Hg to a constant weight of 3.01 g (84. 6£) of
the desired urea, m.p. 190-192° C IR (KBr) 3380, 3320, 2230, "
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1680, 1600, 1540, 1320, 1240 cm" 1 . X E NMR (Me 2 S0-d 6 , 300MHZ) S
2.6-2.7 (d,2H), 4.9-5.1 (m,lH), 6.9 (d,lH), 7.0-7.6 (a, 9H) , 9.0
(s,lH); 13C NMR (Me 2 S0-d 6 , 75.5MHZ) 5 172.8, 154.6, 145.6, 143.3,
134.0, 127.8, 127.1, 120.2, 118.3, 103.4, 50.8, 41.6. Anal.
5 Calcd for C 17 H 15 N 3 0 3 : C, 66.01; H, 4.89; N, 13.59. Found: C,
66.15; H, 4.92; N, 13.92.
EXAMPLE 5
10 Preparation of N-(4-Cyanophenyl)-N'-r3-(3-(3-pyridyl)propionic
acid)]urea Sodium salt
To a solution of 1.66 g (10 mmol) of 3-amino-3-(3-pyridyl)
propionic acid, 0.4 g of NaOH, and 50 ml H 2 0 was added 2.88 g (20
15 mmol) of 4-cyanophenyl isocyanate in 50 ml ethyl acetate. The
reaction mixture was stirred overnight at room temperature. The
two phase mixture was filtered to remove traces of impurities and
the aqueous phase was twice extracted with ethyl acetate. The
water was removed at reduced pressure to produce a gummy mass.
20 TLC and *H NMR indicated the material to be a mixture of desired
urea and starting beta-amino acid. The desired urea was isolated
by reverse phase chromatography using acetoni tile/water as the
mobile phase. IR (KBr) 3400, 2230, 1700, 1600, 1560, 1400 cm" 1 .
X H NMR (Me 2 S0-d 6 , 300MHz) 8 2.5 (d,2H), 5.1 (s,lH), 7.3 (m,lH),
25 7.5 (d,2H), 7.6 (d,2H), 7.65 (s,lH), 8.35 (d,lH), 8.55 (s,lH),
9.3 (d,lH); NMR (Me 2 S0-d 6 , 75.5 MHz) S 174.8, 154.7, 147.8,
147.0, 146.1, 140.7, 133.5, 132.6, 123.0, 119.6, 117.2, 101.0,
49.7, 45.0.
30 EXAMPLE 6
Preparation of N-(4-Nitrophenyl)-N'-[3-(3-phenylpropionic
acid) I urea
35 To a slurry of 1.652 g (10 mmol) of 3-amino-3-phenylpropionic
acid in 50 ml acetone was added 1.641 g (10 mmol) of
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4-ni trophenyl isocyanate dissolved in 5 ml acetone. After 4
hours of stirring at room temperature, a trace of insoluble
impurities was removed by filtration. After removal of the
solvent a bright yellow solid was isolated in a quantitative
5 yield. The crude product was purified on a silica column using a
chloroform: methanol race tic acid solvent. IR (KBr) 3400, 1700,
1560, 1500, 1350 cm" 1 . *H NMR (Me 2 S0-d 6 , 300MHz) 6 2.75 (bs,2H),
5.2 (d,lH), 7.2-7.4 (m,5H), 7.65 (d,2H), 7.85 (m,lH), 8.1 (d,2H),
10.1 (s,lH); 13 C NMR (Me 2 S0-d 6 , 75.5 MHz) 5 153.9, 147.4, 143.3,
10 140.2, 128.1, 126.6, 126.3, 124.9, 116.7, 50.5. Anal. Calcd for
C 16 H 15 N 3 0 5 (2H 2 0): C, 52.59; H, 5.24: N, 11.50. Found: C, 52.14;
H, 4.70; N, 11.56.
EXAMPLE 7
15
Preparation of N-4-Carbamoylphenyl-N / -(3-(3-phenylpropionicacid)
urea
Methyl 3-isocyanato-3-phenylpropionate was first prepared.
20
The reaction assembly is as follows: a 100 mL three-neck
round bottom flask was fitted with a thermometer, reflux
condenser, and gas inlet bubble tube. The condenser was
connected to a trap and then to an aqueous NaOH bath (phosgene
25 scrubber). The gas inlet line consisted of a T-tube with nitrogen
and phosgene inlets at two of the openings. The exit led through
a trap and into the gas bubble tube.
The apparatus was purged with nitrogen, toluene (20 mL) was
added and the solution chilled in an ice-salt bath to 0 °C.
30 Gaseous phosgene (10 mL, 14 g, 140 mmol; actual measurement based
on volume increase of the toluene solution) was added and a slow
addition of phosgene was continued throughout the remainder of
the reaction. Methyl 3-phenyl-3-aminopropionate was added
portionwise over 2 min. to the phosgene solution. The reaction
35 mixture was stirred at 0 °C for 15 min, allowed to warm to room
temperature over 30 min, and then carefully heated and held at
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10
110 °C for 4 hours (slow phosgene addition was continued). The
resulting clear solution vas allowed to cool to room temperature,
purged with nitrogen overnight and then concentrated (asp vacuum)
yielding an oil. Vacuum distillation using a Kugelrohr apparatus
(70 °C, 1 mm) afforded the pure isocyanate (8.95 g, 94 %)• iji
NMR (CDC1 3 ) S 7.42 (m, 5 H), 5.12 (q, J = 4.7 Hz, 1 H) , 3.71 (s,
3 H), 2.79 (m, 2 H); IR (thin film) cm" 1 2251, 1745, 1438,
1269, 1199, 1170, 987, 760, 700. Anal. Calcd for C^H^N^: C,
64.38; H, 5.40; N, 6.83. Found: C, 64.52; H, 5.55; N, 6.81.
r
N-(4-Carbamoylphenyl)-N'-[(3-(methyl 3-phenylpropionate) ] was
then prepared by the following procedure.
To a solution of methyl 3-isocyanato-3-phenylpropionate (1.97
15 g, 9.59 mmol) in CH 3 CN (35 mL) was added 4-aminobenzamide (1.31
g, 9.59 mmol) with stirring at room temperature. The resulting
clear solution was allowed to stand for 3 weeks during which time
a white precipitate formed. Vacuum filtration yielded the desired
urea (3.06 g, 94 %) as a white solid; mp 198-200 °C; 1 R NMR
(DMS0d 6 ) S 8.78 (s, 1 H), 7.71 (d, J = 9.3 Hz, 2 H), 7.37 (d, J
= 9.3 Hz, 2 H), 7.36-7.18 ( m, 5 H), 7.10 (s, 1 H) , 6.88 (d, j'=
7.8 Hz, 1 H), 5.12 (q, J = 7.8 Hz, 1 H) , 3.54 (s, 3 H) , 2.82 (m,
2 H); IR (KBr) cnr* 3354, 1730, 1669, 1659, 1528, 701. Anal.
Calcd for C 18 H 19 N 3 0 4 : C, 63.33; H, 5.61; N, 12.31. Found: C,
25 63.29; H, 5.82; N, 12.43.
LiOH (0.31 g, 7.3 mmol) in H 2 0 (5 mL) was added via syringe
pump over 4 hr to a solution of
N-(4-carbamoylphenyl)-N'-[3-(methyl 3-phenylpropionate)] (2.50 g,
7.32 mmol) in CH 3 OH/H 2 0 (2:1, 75 mL) . The resulting suspension '
was stirred for 36 hr and filtered. The aqueous filtrate was
washed with methylene chloride (3 X 25 mL) and then acidified to
pH 3 with 1 N HC1, yielding the desired acid,
N-(4-carbamoylphenyl)-N'-[3-(3-phenylpropionic acid) Jurea (1. 75
35 g, 73 %) as a white solid: mp 201-212 °C with decomp; iH NMR
(CD3OD) S 8.82 (s, 1 H), 7.76 (s) and 7.71 (d, J = 8.6), (3 H) ,
20
30
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7,37 (d, J « 8.6 Hz, 2 H), 7,34-7.17 (m, 5 H), 7.09 (s, 1 H),
6.87 (d, J = 8.4 Hz, 1 H), 5.13-5.05 (m, 1 H), 2.73 (d, J = 7.0
Hz, 2 H); 13 C NMR (DMS0-d 6 ) 5 172.5, 168.0, 154.5, 143.6, 143.1,
129.0, 128.8, 127.4, 127.1, 126.8, 116.9, 50.4, 41.4. IR (KBr)
5 3343, 1693, 1661, 1649, 1604, 1543, 1414, 1239, 852, 762, 699.
Anal. Calcd for C 17 H 1 7 N 3 0 4 (0.84 H 2 0): C, 59.62; H, 5.50; N,
12.27. Found: C, 59.62; H, 5.26; N, 12,18.
EXAMPLE 8
10
Preparation of N-(4-Sulf onamidophenyl)-N' -[3-(3-phenylpropionic
acid) jurea
Methyl 3-isocyanato-3-phenylpropionate vas prepared by the
15 procedure of Example 7. To a solution of methyl
3-isocyanato-3-phenylpropionate (1.59 g, 7.75 mmol) in
acetonitrile (50 mL) was added sulfanilamide (1.33 g, 7.75 mmol)
in one portion with stirring. The resulting homogenous solution
was allowed to stand for 3 weeks, during which time a white
20 precipitate formed. Vacuum filtration yielded
N-4-sulfonamidophenyl)-N'-[3-(methyl 3-phenylpropionate) Jurea as
a white solid (2.35 g, 80.5 %) . mp 221-222 °C; 1 H NMR (DMS0) 5
8.93 (s, 1 H), 7.63 (d, J = 8.7 Hz, 2 H), 7.49 (d, J = 8.6 Hz, 2
H), 7.38-7.18 (m, 5 H), 7.13 (s, 2 H), 6.93 (d, J = 8.4 Hz, 1 H),
25 5.11 (q, J = 7.5 Hz, 1 H), 3.52 (s, 3 H), 2.93-2.76 (m, 2 H). IR
(KBr)Cm- 1 3800-2800 (br), 1723, 1688, 1682,' 1594, 1392, 1493,
1333, 1239, 1157, 1015, 837, 702, 607. Anal. Calcd for
C 17 H 19 N 3 0 5 S 1 : C, 54.10; H, 5.07; N, 11.13; S, 8.50. Found: C,
54.36; H, 5.22; N, 10.91; S, 8.56.
30
To a stirred solution of methyl ester from above (2.00 g,
5.30 mmol) in methanol/water (3:2, 50 mL) was added LiOH (0.22 g,
5.30 mmol) in water (5 mL) over 4 hr. The resulting suspension
was filtered. The filtrate was washed with methylene chloride (3
35 X 15 mL), and then acidified (1 N HC1) to pH 2 yielding
N-(4-sulfonamidophenyl)-N'-[3-(3-phenylpropionic acid)]urea as a
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white solid (1.08 g, 56 X): mp 165-167 °C with decomposition; *H
NMR (DMS0-d 6 ) S 8.96 (s, 1 H) , 7.62 (d, J = 8.7 Hz, 2 H) , 7.47
(d, J = 8.8 Hz, 2 H), 7.39-7.18 (m, 5 H) , 7.13 (s, 2 H), 6.93 (d,
J = 8.3, 1 H), 5.08 (q, J = 7.8 Hz, 1 H) , 2.73 (d, J = 7.3 Hz, 2
5 H); 13 C NMR (DMS0-d 6 ) 5 40.87, 49.97, 116.83, 126.31, 126.75,
127.00, 128.32, 136.14, 142.54, 143.41, 154.00, 172.04; IR (KBr)
cm- 1 3650-2800 (br) , 1883, 1840, 1592, 1541, 1326, 1155. Anal.
Calcd for C^H^^OgS! (1 H 2 0): C, 50.39; H, 5.02; N, 11.02; S,
8.41. Found: C, 50.75; H, 4.96; N, 10.90; S, 8.31.
10
EXAMPLE 9
Preparation o f N- ( 4-Carbome thoxy phenyl )-N'-[3-( 3-phenylpropionic
acid) ] urea
15
A solution of 3-amino-;3-phenylpropionic acid (3.19 g, 19.3
mmol) and NaOH (0.77 g, 19.3 mmol) in water/acetonitrile (1:1, 20
mL) was added in three portions over 15 min to a vigorously
stirred solution of 4-methoxycarbonylphenyl isocyanate (3.00 g,
20 19.3 mmol) in acetonitrile (20 mL) . The acetonitrile was removed
by rotary evaporation and the resulting aqueous solution was
washed with ethyl acetate (2 X 25 mL) . After acidification of
the aqueous phase (pH 2) with 1 N HC1, the desired urea
precipitated (3.61 g, 55 %) as a white solid: mp 111-112 °C with
25 decomposition; ^ NMR (DMS0-d 6 ) 5 9.01 (s, 1 H), 7.79 (d, J = 8.7
Hz, 2 H), 7.47 (d, J - 8.7 Hz, 2 H), 7.40-7.17 (m, 5 H), 6.95 (d,
J = 8.4 Hz, 1 H), 5.10 (q, J = 7.2 Hz, 1 H) , 3.76 (s, 3 H) , 2.75
(m, 2 H); 13 C NMR (DMS0-d 6 ) 5 172.48, 166.41, 154.39, 145.40,
142.99, 130.79, 128.74, 127.41, 126.76, 122.28, 117.16, 52.08.
30 50.41, 41.31; IR (KBr) cm" 1 3600-2400 (br), 1712, 1657, 1594,
1548, 1436, 1411, 1285, 1245, 1176, 1113, 765, 700. Anal. Calcd
for C 18 H 18 N 2 0 5 : C, 63.15; H, 5.30; N, 8.18. Found: C, 63.09;
H, 5.45; N, 7.89.
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EXAMPLE 10
Preparation of
N-4-(Carboethoxyphenyl)-N , -[3-(3-(3-pyridyl)propionic acid)]urea
5
To a solution of NaHC0 3 (2.13 g, 25.3 mmol) in water (5 mL)
was added 3-amino-3-(3-pyridyl)propionic acid (4-21 g, 25,3
mmol). The resulting solution was concentrated (5 mm vacuum)to
dryness and ethanol was added (20 mL) . This suspension was
10 concentrated (5 mm vacuum) and the ethanol treatment and
concentration was repeated a second time. The white solid thus
formed was suspended in methanol (50 mL) and carboethoxyphenyl
isocyanate (4.84 g, 25.3 mmol) added in one portion which
resulted in the formation of a clear solution. After 4 hr, the
15 solution was concentrated to 15 mL and additional
carboethoxyphenyl isocyanate (1.2 g, 6.3 mmol) was added.
Concentration of this solution (5 mm vacuum) afforded a white
solid. Water (10 mL) was added to the solid and after vigorous
stirring, the suspension was filtered. The filtrate was washed
20 with methylene chloride (2X5 mL) and concentrated (5 mm vacuum)
providing a white foam. This material was purified by reverse
phase high pressure liquid chromatography (100 X water) and
afforded the desired product as sodium salt (white solid): mp
190-195°C with decomposition; 2 H NMR (DMS0-d 6 ) S 10.92 (s, 1 H),
25 8.91 (d, J = 6.0 Hz, 1 H), 8.65 (s, 1 H), 8.40 (d, J = 4.4 Hz, 1
H), 7.79 ( d, J = 8.8 Hz, 3 H), 7.63 (d, J = 8.8 Hz, 2 H) , 7.31
(d of d [J = 4.8 and 7.7 Hz, 1 H), 5.19 (q J = 6.4 Hz, 1 H), 4.26
(q, J = 7.1 Hz, 2 H), 2.60 (m, 2 H), 1.30 (t, J = 7.2 Hz, 3 H);
13 C NMR (DMS0-d 6 ) 8 175.66, 165.98, 155.25, 148.51, 147.57,
30 146.43, 141.05, 134.22, 130.36, 123.51, 121.47, 116.98, 60.35,
50.02, 45.10, 14.55; IR (KBr) cm" 1 3700-2600 (br), 1693, 1597,
1547, 1411, 1285, 1176. Anal. Calcd for C 18 H 18 N 3 0 5 N ai (1.3 H 2 0):
C, 53.68; H, 5.16; N, 10.43. Found: C, 53.66; H, 4.85; N,
10.44.
35
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15
20
25
30
35
EXAMPLE 11
Preparation
of N-(4-C a rbam 0 ylpfaenyl)- N ^ f 3 -(3-(3- D vridvl ) proDionic T ..~-
Procedure A:
A solution of 3-amino-3-(3-pyridyl)propionic acid (4.21 g,
25.3 mmol) in water- '(10 mL) was treated with NaOH (1.01 g, 25.3
mmol) forming the sodium salt. This solution was added to a
solution of 4-carboethoxyphenyl isocyanate (7.62 g, 39.9 mmol) in
acetonitrile (60 mL). After stirring for 2 days, less than 5 %
of the starting amino acid remained unreacted as determined by
HPLC. The resulting suspension was filtered. The remaining
acetonitrile was removed by vacuum evaporation and water (20 mL)
added to the solution. The resulting aqueous solution was washed
with ethyl acetate (3 X 10 mL) and concentrated (5 mm) yielding
the crude product as a gummy oil, *H NMR (DMS0-d 6 ) 5 10.78 (s,
ca. 1 H), 8.73 (d, J = 5.7 Hz, ca. 1 H), 8.58-8.52 (m, 1 H)
8.43-8.32 (m, 1 H), 7.75-7.65 (d, J = 8.6 Hz, 3 H). 7.53 (d' J =
8.6 Hz, 2 H), 7.35-7.20 (m, 1 H), 5.00 (q, J = 6 .7 Hz, 1 H >! 4.20
(q, J = 7.6 HZ, 2 H), 1.52-2.40 (m, 2 H) , 1.24 (t, J = 7 6 Hz 3
H).
To the above crude product (2.5 g, 7.0 mmol) in a Parr Type
high pressure reactor was added NH 4 0H (150 mL, 14.8 M) and the
solution heated to 80 » c for 4.5 hr. The resulting solution was
concentrated yielding a syrup. The syrup was chromatographed on
an HPLC system using Whatman Partisil 20, C 18 packing using 100 %
H 2 0. When the desired product began to elute, the solvent
strength was increased to acetonitrile:water (2.5:97.5). The
fractions containing the product were combined and concentrated
(5 mm) until only about 25 mL of solution remained. This
solution was lyophilized yielding the desired product as a white
solid (0.610 g, 25 X), obtained as a mixture of sodium and
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ammonium salts: 1 E NMR (DMS0-d 6 ) 5 9.52 (s, 1 H), 8*53 (s, 1 H),
8-36 (d, J = 5,7 Hz, 1 H), 8.17 (d, J = 5,7 Hz, 1 H), 7.78-7.62
(m, 4 H), 7.43 (d, J = 8.6 Hz, 2 H), 7.29-7.21 (m, 1 H), 7.05 (s,
1 H), 4.97 (q, J = 6.7 Hz, 1 H), 2.43 (m, 2 H); IR (KBr) cm" 1
5 3600-2800 Cbr), 1663, 1585, 1539, 1412, 1396, 1328, 1316, 1242,
1185, 1115, 851, 769, 711.
Procedure B:
10 Conversion of N-(4-Cyanophenyl)-N' -[3-(3-(3-pyridyl) propionic
acid)] urea to sodium salt of
N-4-Carbamoy lpheny 1-N '-[3-(3-( 3-pyr i dy 1 ) propioni c acid ) ] urea :
Hydrogen peroxide (30%, 3.45 mL, 9.60 mmol) was added to a
stirred suspension of N-(4-cyanophenyl)-N'-[3-(3-
15 (3-pyridyl)propionic acid)]urea was prepared as detailed in
Example 5 and 2.90 g, 9.60 mmol was placed in ethanol (6.9 mL),
water (6.9 mL) and sodium hydroxide (6N, 2.07 mL, 12.42 mmol).
The reaction mixture was stirred for 15 min at room temperature
until the contents of the flask became clear and the evolution of
20 gas (oxygen) stopped. Sodium bisulfite (2g) was added to the
reaction mixture to destroy excess hydrogen peroxide. The
reaction mixture was concentrated in vacuo at room temperature
and then chromatographed (reverse phase HPLC, water as the
eluant). Pure fractions were combined and lyophilized to afford
25 1.90 g (62%) of the desired product as a white crystalline
powder. 1 H NMR (D 2 0) 5 2.70 (d, 2H, J=7.3 Hz), 5.10 (t, 1H,
J=7.1 Hz), 7.33 and 7.68 (AB quartet 4H, J=7.6 Hz), 7.38-7.43 (m,
1H), 7.84 (d, 1H, J=8.0 Hz), 8.39 (d, 1H, J=4.4 Hz), 8.51 (s,
1H). Anal Calcd for C 16 H 15 N 4 Na0 4 (1.5H 2 0) : C, 50.93; H, 4.8: N,
30 14.84. Found: C, 50.83; H, 4.20; N, 14.27
I
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EXAMPLE 12
Preparation of N-(4-Carbo:
acid ) ] urea
>henyl)-N'-[3-(3-(3-pyridyl)proDionic
10
15
20
To a stirred solution of the ethyl ester produced in Example
10 (3-00 g, 7.91 mmol) in water was added NaOH (8.7 mL, 8.7 mmol,
IN). After 20 hr, no starting materials remained as determined
by HPLC. The reaction mixture was concentrated (5 mm vacuum),
dissolved in water (5 mL), filtered (Acrodisc-HPLC filter), and
purified by high pressure liquid chromatography (Whatman
partisil-20, 0DS-3). Concentration (5 mm vacuum) to 50 mL
followed by lyophilization afforded the desired diacid as a white
solid, as the disodium salt; 3 -S NMR (D 2 0 with 5 % DMS0-d 6 ) 8
8.40 (s, 1 H), 8.19 (s, 1 H), 7.80-7.55 (m, 3 H), 7.28-7.07 (m, 3
H), 5.15-4.95 (m, 1 H), 2.73-2.48 (m, 2 H) ; "C NMR (D 2 0 with 5
% DMS0-d 6 ) 5 178.50, 175.05, 156.35, 147.45, 146.82, 141.31,
138.78, 135.18, 130.43, 130.17, 124.33, 118.66, 50.08, 43.97; IR
(KBr) cm- 1 3700-2400 (br), 1688, 1603, 1387, 1311, 1239, 792,
702. Anal. Calcd for C 16 H 13 N 3 0 5 Na 2 (3.51 H 2 0): C, 44,01; H,
4.63; N, 9.62. Found: C, 44.02; H, 4.15; N, 9.71.
EXAMPLE 13
25
Preparati on of N-(4-Iodophenyl)-N'-r3~(3-phenylpropionic
acid) J urea
30
35
To a solution of 4-iodophenyl isocyanate (2.45 g, 10.0 mmol)
in 30 mL of acetonitrile was added a solution of 3-amino-3-
phenylpropionic acid (1.67 g, 10.1 mmol) and sodium hydroxide
(0.404 g, 10.1 mmol) in 10 mL of 1:1 acetonitrile-water.
Precipitation of a white solid made the reaction suspension
difficult to stir, and it was diluted with 10 mL of acetonitrile
and 10 mL of water. The milky white solution was stirred at room
temperature for 16.5 h, and then the acetonitrile removed at
reduced pressure. The aqueous residue was diluted to 150 mL with
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water, and then extracted with three portions of ethyl acetate*
The aqueous solution was made basic with 1 N sodium hydroxide,
then filtered to remove a white solid. The solid was washed with
water and then dried in vacuo at 60 °C. This material, 1.74 g
5 (40%) was identified as the sodium salt of the desired product.
The filtrate was acidified to pH 1 with cone, hydrochloric acid.
The precipitate was filtered, washed with water and ether, then
dried in vacuo at 60 °C to give 1.15 g (28%) of a white solid:
mp: 208-209 °C; X H NMR (300 MHz; DMS0-d 6 ) 5 8.70 (s, 1 H), 7.52-
10 7.20 (AB, 4 H, J AB =8.8 Hz), 7.33-7.28 (m, 5 H), 6.83 (d, 1 H,
J=8.4 Hz), 5.12-5.08 (m, 1 H), and 2.76-2.73 (m, 2 H); 13 C NMR
(75.5 MHz; DMS0-d 6 ) 5 172.2, 154.3, 142.8, 140.3, 137.3, 128.4,
127.1, 126.4, 120.1, 83.9, 50.0, and 41.1; IR (KBr): 3338, 3304,
3064, 3032, 2928, 1705, 1651, 1592, 1547, 1486, 1398, 1314, 1240,
15 and 712 cm" 1 . Analysis: Calculated for C 16 H 15 IN 2 0 3 (H 2 0) 0 37 : C
46.08; H 3.81; N 6.72. Found: C 46.07; H 3.73; N 6.75.
EXAMPLE 14
20 Preparation of N-(4-Chlorophenyl)-N'-[3-(3-phenylpropionic
acid) }urea
To a solution of 4-chlorophenyl isocyanate (1.54 g, 10.0
mmol) in 35 mL of acetonitrile was added a solution of 3-amino-3-
25 phenylpropionic acid (1.67 g, 10.1 mmol) and sodium hydroxide
(0.406 g, 10.2 mmol) in 10 mL of 1:1 acetoni trile-water . The
homogeneous solution was stirred at room temperature for 1.5 h,
and then the acetonitrile removed at reduced pressure. The
aqueous solution was diluted to 150 mL with water, extracted with
30 two portions of ethyl acetate, and then acidified to pH 1 with
cone, hydrochloric acid. The precipitate was filtered, washed
with water, and then dried in vacuo to give 2.82 g (88%) of a
white solid: mp 185-186 °C; X H NMR (300 MHz; DMS0-d 6 ) S 8.74 (s,
1 H), 7.41-7.22 (AB, 4 H, J AB -8.8 Hz), 7.37-7.29 (m, 5 H), 6.84
35 (d, 1 H, J=8.4 Hz), 5.16-5.08 (m, 1 H), and 2.77-274 (m, 1 H);
13 C NMR (75.5 MHz; DMS0-d 6 ) 5 172.2, 154.4, 142.8, 139.4, 128.6,
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20
30
35
128.5, 127.1, 126.4, 124.8, 119.2, 50.1 and 41.1; IR (KBr): 3336,
3304, 3064, 3032, 2928, 1706, 1652, 1595, 1553, 1493, 1398, 1312,
1240, and 704 cm" 1 . Analysis: Calculated for C 16 H 15 C1N 2 0 3 (H 2 0) :
C, 60.05; H, 4.77; N, 8.75- Founds C, 60.05; H, 4.74; N, 8.83.
EXAMPLE 15
Preparation of N-(3-Chlorophenyl)-N f -[3-(3-phenylpropionic
acid) ]urea
To a solution of 3-chlorophenyl isocyanate (1.54 g, 10.0
mmol) in 35 mL of acetonitrile vas added a solution of 3-amino-3-
phenylpropionic acid ( 1.67 g, 10.1 mmol) and sodium hydroxide
(0.436 g, 10.9 mmol) in 10 mL of 1:1 acetonitrile-vater. The
15 homogeneous solution was stirred at room temperature for 3 h,
then concentrated at reduced pressure to afford a yellow oil.
a
This material was dissolved in 100 mL of water, extracted with
two portions of methylene chloride, and then acidified to pH 0-1
with cone, hydrochloric acid. The precipitate was filtered,
washed with water, and dried in vacuo at 60 °C to give 2.86 g
(90%) of a white solid: mp 172-173 °C; *H NMR (300 MHz, DMS0-d 6 )
5 8.84 (s, 1 H), 7.67 (s, 1 H) , 7.37-7.29 (m, 4 H) , 7.24-7.15 (m,
3 H), 6.91 (d, 2 H, J«7.8 Hz), 5.18-5.11 (m, 1 H), and 2.79-2.76
(m, 2 H); NMR (75.5 MHz; DMS0-d 6 ) 5 172.3, 154.4, 142.8,
25 142.0, 133.4, 130.4, 128.5, 127.2, 126.5, 121.0, 117.1, 116.2,
50.2, and 41.1; IR (KBr): 3392, 3064, 3032, 2928, 1717, 1653,
1592, 1552, 1483, 1424, and 700 car'-. Analysis: Calculated for
C 1S H 15 C1N 2 0 3 : C, 60.29; H, 4.74j N, 8.79. Found: C, 60.34; H,
4.70; N, 8.82.
EXAMPLE 16
Preparation of N-(4-Methylphenyl)-N'-r3-(3-phenylpropionic
acid) ]urea
To a solution of 4-methylphenyl isocyanate (1.33 g, 10.0
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mmol) in 35 mL of acetonitrile was added a solution of 3-amino-3-
phenylpropionic acid (1.67 g, 10.1 mmol) and sodium hydroxide
(0.434 g, 10.9 mmol) in 10 mL of 1:1 acetonitrile-vater. The
homogeneous solution was stirred at room temperature for 2.5 h,
then partially concentrated at reduced pressure. The aqueous
solution was diluted with 200 mL of water, extracted with two
portions of ethyl acetate, and then acidified to pH 0-1 with
cone, hydrochloric acid. The precipitate was filtered, washed
with water, and dried in vacuo at 60 °C to give 2.86 g (96%) of a
white solid: mp 169-170 °C; *H NMR (300 MHz; DMS0-d 6 ) S 8.49 (s,
1 H), 7.38-7.20 (m, 5 H), 7.29-7.00 (AB, 4 H, J AB = 8.3 Hz), 6.75
(d, 1 H, J=8.5 Hz), 5.19-5.12 (m, 1 H), 2.78-2.75 (m, 2 H), and
2.19 (s, 3 H); * 3 C NMR(75.5 MHz; DMS0-d 6 ) S 172.3, 154.7, 143.1,
137.9, 130.2, 129.3, 128.5, 127.1, 126.5, 117.9,50.1, 41.3, and
15 20.5; IR (KBr): 3392, 3032, 2928, 1718, 1646, 1601, 1555, 1514,
1408, 1312,1240, 1195, 816, and 712 cnr 1 . Analysis: Calculated
for C 17 H 18 N 2 0 3 : C, 68.44; H, 6.08; N, 9.39. Found: C, 68.38; H,
6.10; N, 9.37.
20 EXAMPLE 17
Preparation of N-(4-Trif luoromethylphenyD-N' -
[3-(3-phenylpropionic acid)]urea
25 To a solution of 4-trif luoromethylphenyl isocyanate (1.87 g,
10.0 mmol) in 35 mL of acetonitrile was added a solution of 3-
amino-3-phenylpropionic acid (1.67 g, 10-1 mmol) and sodium
hydroxide(0.414 g, 10.3 mmol)in 10 mL of 1:1 acetonitrile-vater.
The reaction mixture was stirred at room temperature for 4.5 h,
30 then partially concentrated at reduced pressure. The aqueous
solution was diluted with 150 mL of water and then acidified to
pH 0-1 with cone, hydrochloric acid. The yellow solid that
precipitated was filtered and washed with water. It was then
dissolved in 150 mL of ether and extracted with three portions of
35 aqueous sodium hydroxide. The aqueous solution was acidified to
pH 0-1 with cone, hydrochloric acid. The precipitate was
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filtered, washed with water, and dried in vacuo at 60 °C to give
3.18 g (90%) of a white solid: mp 172-173 °C; !H NMR (300 MHz;
DMS0-d 6 ) 5 9.12 (s, 1 H), 7.59-7.52 (AB, 4 H, J AB =9 2 Hz), 7.38-
7.20 (m, 5 H), 7.04 (d, 1 H, J= 8.5 Hz), 5.18-5.11 (m, 1 H) , and
5 2.79-2.76 (m, 2 H) ; 13 C NMR (75.5 MHz; DMS0-d 6 ) 5 172.2, 154.3,
144.2, 142.8, 128.5, 127.2, 126.5, 126.1, 123.0, 121.4, 117.4,
50.2, and 41.1; IR (KBr): 3360, 3064, 3032, 2928, 1720, 1654,
1602, 1555, 1327, 1248, 1168, 1115, 1072, and 710 cm- 1 . Analysis:
Calculated for C 17 H 15 F 3 N 2 0 3 <H 2 0) 0 . 36 : C, 56.88; H, 4.42; N,
10 7.80; Found: C, 56.87; H, 4.27; N, 7.81.
EXAMPLE 18
Preparation of
15 N-(4-Cyanophenyl)-N |, -[3-(3-(4 , -methoxyphenyl)propionic acid)1urea
To a solution of p-anisaldehyde (40.8 g, 300 mmol) in 100 mL
of 95:5 ethanol-water was added ammonium acetate (46.2 g, 600
mmol). The reaction mixture was warmed to 45 °C, and then treated
20 with malonic acid (31.2 g, 300 mmol) in one portion. The
resulting suspension was heated at reflux for 18 h, allowed to
cool to room temperature, and filtered. The precipitate was
recrystallized from 3:1 ethanol-water to give 30.9 g (53£) of a
white solid 3-amino-3-(4'-methoxyphenyl)propionic acid: mp 234-
25 235 °C; *E NMR (300 MHz; H0Ac-d 4 ) 5 7.45-6.95 (AB, 4 H, J AB =8.6
Hz), 4.76 (dd, 1 H, J-9.1, 5.2 Hz), 3.79 (s, 3 H) , 3.24 (dd, 1 H,
J=17.3, 9.1 Hz), and 2.97 (dd, 1 H, J=17.3, 5.2 Hz); "C NMR(75.5
MHz; H0Ac-d 4 ) S 176.2, 161.2, 129.7, 128.4, 115.1, 55.1, 52.8,
and 38.9; IR (KBr): 3424, 2937, 2616, 1613, 1535, 1518, 1407,
30 1251, 1184, 1027, and 838 cur 1 . Analysis Calculated for
C 10 H 13 N0 3 : C, 61.53, H, 6.71; N, 7.18. Found: C, 61.86; H, 6.56;
N, 7.10.
To a solution of 4-cyanophenyl isocyanate (1.44 g, 10.0 mmol)
35 in 35 mL of acetonitrile was added a solution of 3— amino— 3— (4'—
*
me thoxy phenyl) propionic acid (1.97 g, 10,1 mmol) and sodium
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hydroxide (0.430 g, 10.8 mmol) in 10 mL of 1:1 acetoni trile-
water. The resulting milky white solution was stirred at room
temperature for 4 h and then partially concentrated to remove the
acetoni trile* The aqueous solution was diluted with 200 mL of
5 water and acidified to pH 1.5 with cone, hydrochloric acid. The
precipitate was filtered, washed with water and ether, and then
dried in vacuo to give 2.60 g {11%) of an off white solid: mp
105-107 °C; iH NMR (300 MHz; DMS0-d 6 ) 6 9.09 (s, 1 H) , 7.66-7.52
(AB, 4 H, J AB =8.8 Hz), 7.28-6.87 (AB, 4 H, A=7.24, B=6.90,
10 J AB =8.7 Hz), 6.95 (d, 1 H, J=8.4 Hz), 5.09-5.02 (m, 1 H), 3.71
(s, 3 H), and 2.81-2.67 (m, 2 H); 13 C NMR (75.5 MHz; DMS0-d 6 ) S
172.2, 158.3,153.8, 144.8, 134.4, 133.2, 127.6, 119.5, 117.5,
113.7, 102.6, 55.1, 49.5, and 40.9; IR (KBr): 3360, 2225, 1716,
1675, 1593, 1537, 1514, 1319, 1250, 1233, 1176, 838, and 548
15 cm- 1 . Analysis: Calculated for C 18 H 17 N 3 0 4 (H 2 O) 0>88 : C, 60.87; H,
5.32; N, 11.83. Found: C, 60.84; H, 5.41; N, 12.04.
EXAMPLE 19
20 N-(4-Cyanophenyl)-N , -[3-(3-(2 , -naphthyl)propionic acid) lurea
To a solution of 2-naphthaldehyde (15.6 g, 100 mmol) in 50 mL
of 9:1 ethanol-water was added ammonium acetate (15.4 g, 200
mmol). The reaction mixture was warmed to 45 °C, and then treated
25 with malonic acid (10.4 g, 100 mmol) in one portion. The
resulting suspension was heated at reflux for 16 h, then cooled
and filtered. The precipitate was recrystallized from 4:1
ethanol-water to give 14.6 g (68%) of a white solid,
3-amino-3-(2'-naphthyl)propionic acid: mp 225-227 °C; 1 H NMR (300
30 MHz; TFA-d x ) 5 7.59-7.43 (m, 4 H), 7.17-7.14 (m, 2 H) , 7.07-7.05
(d, 1 H, J=7.8 Hz), 4.69 (dd, 1 H, J=10.0, 4.0 Hz), 3.18 (dd,l H,
J=18.4, 10.0 Hz), and 2.88 (dd, I H, J=18.4, 4.0 Hz); 13 C NMR
(75.5 MHz; TFA-d x ) 5 179.2, 136.6, 135.6, 132.5, 131.9, 130.2,
130.0, 129.8, 129.5, 124.6, 56.2, and 38.5; IR (KBr): 3424, 2936,
35 2616, 1626,1585, 1515, 1388, 1327,1274, 823, and 745 cur 1 .
Analysis: Calculated for C 13 H 13 N0 2 (H 2 0) 0 . 05 : C, 72.24; H, 6.11;
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10
N, 6.48. Found: C. 72.22; H. 6.13; N. 6.24.
To a solution of 4-cyanophenyl isocyanate (1.44 g, 10.0 mmol)
in 35 mL of acetonitrile vas added a slurry of 3-amino-3-(2'-
naphthyl) prop ionic acid (2.17 g, 10.1 mmol) and sodium hydroxide
(0.447 g, 11.2 mmol) in 20 mL of 1:1 acetonitrile-water. The
resulting white suspension was stirred at room temperature for 2
h and then heated at reflux for 2 h. The reaction solution was
partially concentrated at reduced pressure to give an aqueous
suspension, which vas acidified to pH 1.5 with cone, hydrochloric
acid. The suspension was filtered to give 3.1 g of a pale yellow
solid. This material was recrystallized from 1:1 methanol-water
to afford 1.46 g (41X) of a white solid: mp 203-204 °C; *-E NMR
(300 MHz; DMS0-d 6 ): 12.39 (br s, 1 H), 9.21 (s, 1 H), 7.90-7.86
15 (m, 4 H), 7.67-7.56 (AB, 4 H, J AB =8.8 Hz), 7.56-7.44 (m, 3 H) ,
7.18 (d, 1 H, J=8.4 Hz), 5.36-5.29 (m, 1 H), and 2.93-2.89 (m, 2
H); 13 C NMR (75.5 MHz; DMS0-d 6 ): 172.1, 153.9, 144.8, 140.0,
133.2, 132.8, 132.2, 128.0, 127.7, 127.5, 126.3, 125.8, 125.0,
124.7, 119.5, 117.5, 102.6, 50.2, and 40.7; IR (KBr): 3376, 3312,
2948, 2224, 1698, 1656, 1589, 1547, 1409, 1318, 1229, and 1175
cm-i. Analysis: Calculated for C 21 H 17 N 3 0 3 (H 2 0) 0 . 1X : C, 69.80; H,
4.80; N, 11.63. Found: C, 69.79; H, 4.62; N, 11.64.
20
25
30
EXAMPLE 20
N-(4-Cyanopheny l)-N'-r3-(3-(3',4'-dimethoxyphenyl)propionic
acid) Jurea
To a solution of 3,4-dimethoxybenzaldehyde (16.6 g, 100 mmol)
in 50 mL of 9:1 ethanol-water was added ammonium acetate (15.4 g,
200 mmol). The reaction mixture was warmed to 45 °C, and then
treated with malonic acid (10.4 g, 100 mmol) in one portion. The
suspension was heated at reflux for 16.5 h, then cooled and
filtered. The precipitate was washed with several portions of
35 ether and then dried in vacuo at 60 °C to yield 12.1 g (54£) of a
white solid, 3-amino-3-(3',4'-dimethoxyphenyl)propionic acid: mp
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216-217 °C; X H NMR (300 MHz; D 2 0) 5 6.93 (s, 1 H), 6.90 (s, 2 H),
4.44 (dd, 1 H, J-8-0, 6.6 Hz), 3.72 (s, 3 H), 3,69 (s, 3 H), 2.75
(dd, 1 H, J=16.2, 6.6 Hz), and 2.64 (dd, 1 H, J=16.2, 8.0 Hz);
13 C NMR (75.5 MHz; Ac0H-d 4 ) S 176.1, 150.6, 150.2, 128.9, 120.9,
5 112.5, 111.6, 56.0, 53.2, and 39.0; IR (KBr): 3424, 2935, 2836,
1604, 1574, 1552, 1523, 1465, 1396, 1273, 1148, and 1025 cm" 1 .
Analysis: Calculated for C 1:L H 15 N0 4 : C, 58.66; H, 6.71; N, 6.22.
Found: C, 58.42; H, 6.63? N, 6.15.
10 To a solution of 4-cyanophenyl isocyanate (1.08 g, 7.50 mmol)
in 40 mL of acetonitrile was added a solution of 3-amino-3-
(3' ,4'-dimethoxyphenyl)propionic acid (1.71 g, 7.58 mmol) and
sodium hydroxide (0.309 g, 7.72 mmol) in 5 mL of water. The
reaction mixture was stirred for 3.5 h at room temperature and
15 then partially concentrated at reduced pressure. The aqueous
solution was diluted with 100 mL of water and then acidified to
pH 2 with cone, hydrochloric acid, resulting in formation of a
gum. The liquid was decanted and the gummy residue was dissolved
with aqueous sodium hydroxide. The basic solution was washed with
20 portions of ether and methylene chloride, then acidified to pH 2
with cone, hydrochloric acid, resulting in formation of a gum.
The aqueous solution was diluted with 15 mL of methanol and then
warmed gently until the gum solidified. The precipitate was
filtered, washed with water, and dried in vacuo at 60 °C to give
25 2.00 g (72%) of a white solid: mp 148-150 °C; 1 H NMR (300 MHz;
DMS0-d 6 ) S 12.30 (br s, 1 H), 9.11 (s, 1 H), 7.66-7.53 (AB, 4 H,
J AB =8.8 Hz), 6.99-6.83 (m, 4 H), 5.09-5.02 (m, 1 H) , 3.74 (s, 3
H), 3.71 (s, 3 H), and 2.76-2.73 (m, 2 H) ; 13 C NMR (75.5 MHz;
DMS0-d 6 ) 8 172.2, 153.8, 148.6, 147.9, 144.9, 135.0, 133.2,
30 119.5, 118.3, 117.5, 111.7, 110.5, 102.6, 55.6, 49.9, and 41.1;
IR (KBr): 3360, 2224, 1704, 1594, 1518, 1411, 1319, 1233, 1145,
1024, 848, and 552 cm" 1 . Analysis: Calculated for C 19 H 19 N 3 0 5
( H 2°)o.86 s c > 59.30; H, 5.43; N, 10.92. Found: C, 59.27; H, 5.07;
N, 10.88.
35
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EXAMPLE 21
10
Preparation
o f N- ( 4-Cyanopheny 1 )-N'-[3-(3-(3'-4' -me thy lened i oxyphenyl Y
propionic acid)]urea
To a solution of piperonal (15.0 g, 100 mmol) in 50 mL of 9:1
ethanol-water was added ammonium acetate (15.4 g, 200 mmol). The
reaction mixture was warmed to 45 °C, and then treated with
malonic acid (10.4 g, 100 mmol) in one portion. The suspension
was heated at reflux for 16 h, cooled to 0 °C, and filtered. The
precipitate was washed with ethanol and ether, and then dried in
vacuo at 60 °C to give 7.32 g (ca 35Z) of a yellow solid. This
material consisted of a 91:9 mixture of the desired g-amino acid
15 [3-amino-3-(3' ,4'-methylenedioxyphenyl)propionic acid] and an
a, ^-unsaturated acid; it was used in the next reaction without
further purification. *H NMR (300 MHz; Ac0H-d 4 ): 7.01 (s, 1 H),
6.99-6.82 (AB, 2 H, J AB =8 0 Hz), 5.97 (s, 2 H), 4.75 (dd, 1 H,
J-9.1, 5.4 Hz), 3.23 (dd, 1 H, J=17.3, 9.1 Hz), and 2.97 (dd, 1
20 H, J=17.3, 5.4 Hz).
To a solution of 4-cyanophenyl isocyanate (1.08 g, 7.50 mmol)
in 40 mL of acetonitrile was added a solution of 3-amino-3-
(3' ,4'-methylenedioxyphenyl)propionic acid (1.81 g, 7.88 mmol)
25 and sodium hydroxide (0.360 g, 9.00 mmol) in 5 mL of water. The
suspension was stirred at room temperature for 1.25 h and then
filtered. The solid was suspended in 50 mL of water and the
solution acidified to pH 2 with cone, hydrochloric acid. The
precipitate was filtered, washed with water, and dried in vacuo
at 60 °C to give 1.73 g (65£) of a white solid: mp 189-191 °C; *H
NMR (300 MHz; DMS0-d 6 ) S 12.3 (br s, 1 H) , 9.14 (s, 1 H) , 7.66-
7.52 (AB, 4 H, J=8.7 Hz), 7. 00 (d, 1 H, J=8.4 Hz), 6.93 (s, 1 H),
6.86-6.81 (m, 2 H) , 5.97 (s, 2 H) , 5.06-4.98 (m, 1 H),and 2.80-
2.65 (m, 2 H); 13 C NMR (75.5 MHz; DMS0-d 6 ) S 172.1, 153.8, 147.3,
35 146.2, 144.8,136.6, 133.2, 119.6, 119.5, 117.5, 108.0, 107.0,
102.6, 101.0, 49.9, and 41.0; IR (KBr):3060, 2225, 1714, 1675,
30
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1593, 1537, 1505, 1444, 1412, 1317, 1238, 1176, 1040, 840, and
552 cnr 1 . Analysis: Calculated for C la H 15 N 3 0 5 (H 2 0) 0 80 : C,
58-79; H, 4.55; N, 11.43. Found: C, 58-77; H, 4.30; N, 11,40.
5 EXAMPLE 22
Preparation of N-(4-Cyanophenyl)-N'-[3-(3-cyclooctylpropionic
acid) jurea
10 A suspension of 3-amino-3-cyclooctylpropionic acid (1.99 g ?
10.0 mmol) and 4-cyanophenyl isocyanate (1.44 g, 10.0 mmol) in
100 mL of acetonitrile was stirred for two hours at room
temperature. The reaction mixture was then heated at reflux until
a clear solution formed. The solution vas allowed to cool and
15 stirred overnight at room temperature. The reaction mixture vas
filtered to yield a crude product which was slurried in ether,
filtered, and dried to a constant weight of 3.1 g (90%) of a
white solid: IR (KBr) cm" 1 3360, 3100, 2920, 2380, 2240, 1760,
1680, 1600, 1540; 1 H NMR (DMS0-d 6 ) S 8.9 (s, 1H), 7.5 (dd, 4H,
20 J=9.7Hz, J-28.6HZ), 6.0 (d, 1H, J=9.2Hz), 3.9 (m, 1H), 2.4 (dd, 2
H, J=4.6, J=14.6Hz), 1.2-1.8 (m, 15H); 13 C NMR (DMS0-d 6 ) S 176.5,
157.7, 148.5, 136.7, 123.0, 120.8, 105.9, 55.4, 40.7, 33.0, 31.5,
30.0, 29.6, 29.4, 28.7. Anal. Calcd for C 19 H 25 N 3 0 3 : C, 66.45; H,
7.34; N, 12.12. Found: C, 66.39; H, 7.21; N, 12.24.
25
EXAMPLE 23
Preparation of N-(4-Cyanophenyl)-N / -[3-(3-phenylpropionic
acid) ] thiourea.
30
To a stirred suspension of 4-cyanophenyl isothiocyanate (1.60
g, 10.0 mmol) and 3-amino-3-phenylpropionic acid (1.65 g, 10.0
mmol) in 50 mL of acetonitrile vas added 10 mL of 1 N NaOH. The
clear yellow solution which immediately formed was stirred
35 overnight and the solvent then removed under reduced pressure.
The residue was dissolved in 50 mL of 1:1 ethyl acetate/water and
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the aqueous layer was extracted tvice with 50 mL ethyl acetate.
The product was precipitated from the aqueous layer as a gum
after adjusting the pH to 2.5 with 4 N HC1. The gummy product was
stirred overnight in water to produce a fluffy white solid. The
5 solid was isolated by filtration and dried to yield 2.65 g (82%)
of the desired product as a off-white powder: IR (KBr) cm -1 3320,
3150, 2235, 1733, 1604, 1542, 1519, 1509,1169; *H NMR (DMS0-d 6 ) 5
10.2 (s, 1H), 8.7 (d, 1H, J=8.3Hz), 7.7 (dd, 4H, J-8.3, J=24Hz),
7.2-7.5 (m, 5H), 5.8 (q, 1H, J=7.3Hz), 2.9 (dd, 2H, J-7.3,
10 J=16Hz); 13 C NMR (DMS0-d 6 ) S 184.6, 177.0, 149.3, 146.3, 137.8,
133.4, 132.3, 131.9, 126.3, 124.2, 109.9, 59.1. Anal. Calc. for
C l7 H 15 N 3 S0 2 : C,62.75; H,4.65; N, 12.91. Found: C,62.60; H,4.78;
N, 12.61.
15 EXAMPLE 24
Preparation of N-(4-C y anophen y l)-N'-[3-(3-(3-quinolyl)propionic
acid) ]urea
20 To a stirred suspension of 4-cyanophenyl isocyanate (1.0 g,
7.0 mmol) and 3-amino-3-(3-quinolyl) propionic acid (1.0 g, 4.6
mmol) in 50 mL of acetonitrile was added 5 mL of 1 N NaOH. The
reaction mixture was stirred overnight before the solvent was
removed at reduced pressure. The residue was dissolved in 100 mL
25 of equal parts of ethyl acetate and water. The aqueous layer was
washed with 50 mL of ethyl acetate and stripped under vacuum to
remove traces of ethyl acetate. The pH of the solution was
adjusted to 4 with diluted HC1 where an oil separated out. The
oil was stirred overnight in 25 mL of fresh water. The thick oil
was placed in a vacuum oven and thoroughly dried to a glassy
solid (525 mg, 31%) t IR (KBr) cm" 1 3360, 3060, 2222, 1703, 1594,
1583, 1317,1226; NMR (DMS0-d 6 ) 8 9.3 (m, 1H) , 9.0 (s, 1H) , 8.4
(s, 1H), 7.9 (t, 2H, J=7.8Hz), 7.7 (t, 1H, J=7.8Hz), 7.6 (m, 3H),
7.5 (d, 2H, J=8.7Hz), 7.3 (d, 1H, J=8.7Hz), 5.4 (q, 1H), 3.0 (d,
35 2H, J=6.8Hz): 13 C NMR (DMS0-d 6 ), 5 173.0, 155.2, 150.3, 146.0,
145.9, 137.0, 136.1, 134.4, 132.2, 129.4, 128.7, 128.4, 120.s!
30
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118.7, 103.9, 49.5. Anal- Calcd for C 2 0 H X 6 N 4 0 3 (1 . 25H 2 0) : C,62.74;
H,4.87; N, 14*63* Found: C.62.72; H,4.84; N, 14.28.
EXAMPLE 25
5
Preparation
of N- ( 4-Me thoxy carbonylphenyl )-N ' - [ 3- ( 3-pheny lpropioni c
acid) ] thiourea
10 To a stirred suspension of 4-methoxycarbonylphenyl
isothiocyanate (1.93 g, 10.0 mmol) and 3-amino-3-phenylpropionic
acid (1.65 g, 10.0 mmol) in 60 mL of acetonitrile was added 10 mL
of 1 N NaOH. The yellow solution was stirred for one hour before
the solvent was removed under vacuum. The residue was dissolved
15 in 200 mL of 50/50 ethyl acetate: water and the aqueous phase
extracted with ethyl acetate (2 x 100 mL). The product was
separated from the aqueous layer as a gum after adjusting the pH
to 2 with 1 N HC1. The gum was stirred in water over the weekend
and the product (2.0 g, 55%) isolated by filtration as a fine
20 white powder: mp 144-6°C; 1 E NMR (DMS0-d 6 ) 5 10.0 (s, 1H), 8.6
(s, 1H), 7.9 (d, 2H, J-8.7Hz) 7.4 (m, 5H), 5.9 (q, 1H, J=6.8Hz),
3.8 (s, 1H), 2,9 (dd, 2H, J=6.8, J=16.5Hz); 13 C NMR (DMS0-d 6 ) S
184.2, 176.6, 170.5, 148.9, 145.9, 134.5, 132.9, 131.7, 131.4,
128.6, 125.4, 58.6, 56.6, 44.6. Anal. Calcd for C x 8 H X 8 N 2 0 4 S(0. 25
25 H 2 0): C,59.45; H,5.15; N,7.70. Found: C,59.44; H,5.06; N,7.62.
EXAMPLE 26
Preparation of N-(4-Cyanophenyl)-N' -[3-(3-cyclohexylpropionic
30 acid) ]urea
A suspension of 3-amino-3-cyclohexanepropionic acid (2.27 g,
13.2 mmol) and 4-cyanophenyl isocyanate (1.90 g, 13.2 mmol) in
100 mL of acetonitrile was stirred for 1 hour. The reaction
35 mixture was then heated at reflux until a clear solution formed.
The solution was allowed to cool and stirred overnight at room
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temperature. The cooled reaction mixture was filtered to yield a
white solid which was dried to constant weight under vacuum. The
crude product was stirred in 1 N NaOH, filtered, and the filtrate
extracted with CHC1 3 (3 x 50 mL) . The pH of the filtrate was
adjusted to 2 with concentrated HC1 and the resulting white solid
isolated by filtration. After drying, the solid was
recrystallized from 125 mL of acetonitrile to yield 2.1 g (502)
of the desired product as a white crystalline solid: IR (KBr)
cm- 1 3320, 2940, 2860, 2240, 1720, 1680, 1600, 1540; *H NMR
(DMS0-d 6 ) S 8.6 (s, 1H), 7.1-7.3 (dd, 4H, J=8.3 Hz, J=30.5Hz),
6.0 (d, 1H, J=9.2Hz),3.5 (m, 1H), 1.9-2.2 (m, 2H) , 0.5-1.4 (m,
11H); 13C NMR (DMS0-d 6 ) S 173.5, 154.7, 145.5, 133.7, 120.0,
117.8, 102.8, 51.2, 41.8, 37.6, 29.8, 28.7, 26.5, 26.3, 26.3.
Anal. Calcd for C 17 H 21 N 3 0 3 : C, 64.745; H, 6.712; N, 13.324.
15 Found: C, 64.67; H, 6.73? N, 13.49.
10
EXAMPLE 27
Preparation of
20 N-(4-C y ano phenyl)-N > -[3-(3-(3 f -nitrophenvl)propionic acid)lurea
To a solution of 4-cyanophenyl isocyanate (2.16 g, 15.0 mmol)
in 50 mL of acetonitrile was added a solution of
3-amino-3-(3'-nitrophenyl)propionic acid (2.10 g, 15.0 mmol) in
25 25 mL of water and 10.0 mL of 1 N NaOH. The reaction mixture was
stirred overnight at room temperature before the solvents were
removed at reduced pressure. The residue was dissolved in 75 mL
of ethyl acetate and 75 mL of water and the ethyl acetate phase
extracted with 0.1 N NaOH (2 x lOOmL) . The combined aqueous
extracts were acidified with 4 N HC1 and the desired product
isolated by filtration (0.83 g, 23%) as a white fluffy powder: mp
173-6°C; IR (KBr) cnr* 3380, 3100, 2225, 1722, 1683, 1662, 1594,
1532, 1411, 1351, 1320,1238; *H NMR (DMS0-d 6 ) S 9.3 (s, 1H), 8.3
(s, 1H), 8.1 (d, 1H, J=7.5Hz), 7.8 (d, 1H, J=7.3Hz), 7.5-7.7 (m,
35 5H), 7.3 (d, 1H, J=7.3Hz), 5.2 (q, 1H, J=7.3Hz), 2.9 (d, 2H,
J=6.1Hz); 13 C NMR (DMS0-d 6 ) S 171.8, 154.1, 148.1, 145.3, 144.7,
30
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133-6, 133.3, 130-0, 122.2, 121.1, 119.4, 117.8, 112.5, 49.4.
Anal. Calcd for C 17 H 14 N 4 0 5 : C, 57.63; H, 3.98; N, 15.81. Found:
C, 57.08; H, 4.05; N, 15.56.
5 EXAMPLE 28
Preparation of N-(4-Cyanophenyl)-N'-[3-(3-(4-pyridylpropionic
acid)]urea Sodium salt
10 To a stirred suspension of 3-amino-3-(4-pyridyl)propionic
acid (0.17 g, 1.0 mmol) and 4-cyanophenyl isocyanate (0.45 g, 3.0
mmol) in 25 mL of acetonitrile was added 1.0 mL of 1 N NaOH and 5
mL of water. The clear solution was stirred for one hour before
the solvents were removed at reduced presssure. The residue was
15 dissolved in 75 mL of 50/50 ethyl acetate:water and the aqueous
phased washed with ethyl acetate (2 x 50mL). The crude product
(0.32 g) was isolated by lyophilization of the aqueous phase and
purified by reverse phase chromatography to yield 0.12 g (36%) of
a white powder: 1 U NMR (DMS0-d 6 ) S 9.25 (bs, 1H), 8.4 (d, 2H,
20 5.8Hz), 7.7 (d, 2H, J=8.7Hz), 7.5 (d, 2H, J=8.7Hz), 7.3 (d, 2H,
J=5.8Hz), 5.0 (q, 1H, J=5.8Hz), 2,4 (m, 2H); NMR S 174.2,
155.0, 154.6, 149.2, 146.5, 132.7, 121.5, 119.6, 117.3, 101.2,
51.5, 44.6.
25 EXAMPLE 29
Preparation of N-(4-Carboxyphenyl)-N'-[3-(3-phenylpropionic
acid) ]urea
30 To a stirred solution of NaOH (0.224 g, 5.60 mmol) in 20 mL
of 1/1 MeOH/water was added to the urea prepared in Example 1.
(0.500 g, 1.40 mmol). After 3 h, the reaction mixture was
partially concentrated to remove the MeOH. The reaction mixture
was diluted to a volume of 50 mL with water and acidified with 6
35 mL of 1 N HC1. The precipitate was isolated by filtration and
air-dried to afford 0.44 g (96%) of . the urea as a white powder:
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mp 190-195 °C; NMR (DMS0-d 6 ) 6 12.43 (br s, 2 H) , 9.0 (s, 1
H), 7.9-7.74 (m, 2 H) , 7.55-7.2 (m, 7 H), 6.96 (d, J= 8.4 Hz, 2
H), 5.2-5.05 (m, 1 H) , 2.9-2.7 (m, 2 H); NMR (DMS0-d 6 ) &
172.0, 167.0, 153.9, 144.6, 142.6, 130.5, 128.3, 127.0, 126.3,
5 122.9, 116.6, 49.9, 40.8? IR(KBr) cm" 1 3460, 3080, 3040, 1700,
1590, 1500, 1390, 1310, 1280, 1240, 1175. Anal. Calcd for
c i7Hi 6 N 2 0 5 -(0.13 H 2 0): C, 61.72; H, 4.96; N, 8.47. Found: C,
61.71; H, 4.87; N, 8.73.
10 EXAMPLE 30
■ — - r
Preparation of N-(Phen y l)-N'-[3-(3-phenylpropionic acid)lurea
The urea was prepared analogously to N-(4-bromophenyl)-N'-(2-
15 carboxy-l-phenylethyl)urea except phenyl isocyanate was
substituted for 4-bromophenyl isocyanate to afford 2.69 g (91%)
of the urea as a powder: mp 179-180 °C; 1 E NMR (DMS0-d 6 ) 5 12.30
(br s, 1 H, NH), 8.58 (s, 1 H) , 7.6-7.1 (m, 8 H), 7.0-6.75 (m, 2
H), 5.17-5.10 (overlapping dt, 1 H), 2.9-2.7 (ra, 2 H) ; "C NMR
(DMS0-d 6 ) 5 172.1, 154.4, 142.9, 140.3, 128.7, 128.4, 126.9,
126.3, 121.2, 117.6, 49.9, 41.1; IR (KBr) cm" 1 3360, 3060, 3020,
1718, 1640, 1600, 1560, 1500, 1460, 1400, 1310, 1240. Anal. Calcd
for C 16 H 1S N 2 0 3 : C, 67.59; H, 5.67; N, 9.85. Found: C, 67.56; H,
5.58; N, 9.76.
20
25
EXAMPLE 31
30
Preparatio n of N-(4-Formylphenyl)-N'-r3-(3-phen y lpropionic
acid) ]urea
To a stirred solution (slightly cloudy) of 1,1'-
carbonyldi imidazole (5.27 g, 32.5 mmol) and imidazole (3.32 g,
48.7 mmol) in 50 mL of dry THF cooled in an ice bath was added a
solution of methyl 3-amino-3-phenylpropionate (5.82 g, 32.5 mmol)
35 in 10 mL of THF over 15 minutes. The reaction solution was
stirred an additional 15 minutes, then a solution of 4-
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aminobenzyl alcohol (4.00 g, 32.5 mmol) in 25 mL of THF was
rapidly added. After an additional 30 minutes, the cooling bath
was removed and the reaction mixture was stirred for 17 hours.
The reaction mixture was then concentrated, the residue dissolved
5 in 100 mL of CH 2 C1 2 and washed with water (100 mL). The aqueous
wash was extracted with CH 2 C1 2 (50 mL) and the organic layers
combined, dried (MgS0 4 ) , and concentrated to afford 9.27 g of
crude product. The crude product was purified by flash
chromatography (silica gel, 4-6% Me0H/CH 2 Cl 2 ) to afford 3.5 g
10 (33%) of N-(4-hydroxymethylphenyl)-N'-[3-(methyl 3-phenyl-
propionate) ]urea as a very pale yellow solid: mp 108-118 °C; TLC
(1/9 CH 3 0H/CH 2 C1 2 , UV) R f = 0.44; 1 E NMR (DMS0-d 6 ) 5 7. 69 (s, 1
H, NH), 7.03, 7.98 (AB quartet, J= 8.6 Hz, 4 H) , 7.3-7.1 (m, 5
fi), 6.48 (d, J= 8.3 Hz, 1 H, NH), 5.35-5.2 (m, 1 H), 4.38 (s, 2
15 H, CH 2 0), 3.5 (s, 3 H, C0 2 CH 3 ), 2.85-26 (m, 2 H, CH 2 ); " C NMR
(DMS0-d 6 ) S 171.7, 155.5, 141.3, 138.1, 135.2, 128.6, 127.7,
127.4, 126.1, 119.8, 64.4, 51.8, 50.6, 41.0; IR (KBr) cm" 1 3340
(br), 1735, 1690, 1660, 1600, 1550, 1513, 1440, 1418. Anal. Calcd
for C 18 H 20 N 2 0 4 : C, 65.84; H, 6.14; N, 8.53. Found: C, 65.94; H,
20 6.20; N, 8.84.
To a stirred solution of N-(4-hydroxymethylphenyl)-N'-
[3-(methyl 3-phenylpropionate) Jurea (2.30 g, 7.01 mmol) in 230 mL
of CH 2 C1 2 was added Mn0 2 (3.00 g, 34.5 mmol) as a solid in one
25 portion. The reaction suspension was stirred for 44 h, then
filtered through celite. The filtrate was concentrated and the
residue purified by flash chromatography (3/7 EtOAc/hexane,
silica gel) to afford 1.14 g (50%) of the desired
N-(4-Formylphenyl)-N'-[ 3- (methyl 3-phenylpropionate) Jurea. An
30 additional 0.518 g (23%) of material was obtained from copious
washing of the celite cake with CH 2 C1 2 , CH 3 CN, and EtOH followed
by flash chromatography purification: TLC (0.5/9.5 CH 3 0H/CH 2 C1, ,
UV) R f = 0.38; *H NMR (DMS0-d 6 ) S 9.79 (s, 1 H, CH0), 9.11 (s f 1
H), 7.76 (d, 2 H, J= 8.6 Hz), 7.57 (d, 2 H, J= 8.6 Hz), 7.4-7.2
35 (m, 5 H), 7.02 (d, 1 H, J= 8.4 Hz, CHNH) , 5.18-5.10 (m, 1 H, CH),
3.54 (s, 3 H, C0 2 CH 3 ), 2.95-2.82 (m, 2 H); 13 C NMR (DMS0-d 6 ) 5
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10
191.3, 170.9, 153.8, 146.2, 142.1, 131.1, 129.6, 128.4, 127.2,
126.3, 117.0, 51.5, 50.0, 40.6; IR (KBr) cm" 1 3370, 3320, 1727,
1687, 1669, 1595, 1560, 1544, 1435, 1365, 122, 1165; TLC (3/7
EtOAc/hexane) R f = 0.48. Anal. Calcd for C 13 H 18 N 2 0 4 : C, 65.70; H,
5.61; N, 8.51. Found: C, 65.68; H, 5.47; N, 8.12.
To a stirred suspension of N-(4-f ormylphenyl)-N-[3-(methyl
3-phenylpropionate) Jurea (1.14 g, 3.49 ramol) in 230 mL of MeOH
and 50 raL of water was added 14 mL of 1 N NaOH (14 mmol). The
reaction mixture became homogeneous after 1 h. After 3.5 hours,
the reaction solution was concentrated to remove the MeOH, and
diluted to a total volume of 250 mL with water. This solution was
washed with EtOAc (100 mL). The aqueous layer was partially
concentrated to remove traces of EtOAc and the pH adjusted to 1
15 with 17 mL of 1 N HC1. A gum formed and the suspension was
stirred overnight. The gum had solidified and the resulting solid
was isolated by filtration. The white powder was dried in vacuo
(<0.2 mm, 40 °C) to afford 1.06 g (97Z) of the desired urea : mp
145-148 °C; *H NMR (DMS0-d 6 ) 5 12.35 (br s, 1 H) , 9.79 (s, 1 H,
20 CH0), 9.15 (s, 1 H, NH), 7.76 (d, 2 H, J= 8.5 Hz), 7.57 (d, 2 H,
J= 8.5 Hz), 7.45-7.2 (m, 5 H, Ph), 7.04 (d, 1 H, J= 8.4 Hz), 5.2-
5.05 (m, 1 H), 2.9-2.7 (m, 2 H) ; 13 C NMR (DMS0-d 6 ) 6 191.5,
191.0, 172.0, 153.8, 146.2, 142.5, 131.1, 129.6, 128.4, 126.4,
117.0, 50.0, 40.8; IR (KBr) cm" i* 3400, 3360, 3060, 1720, 1690,
25 1673, 1660, 1560, 1540, 1166. Anal. Calcd for C 17 H 16 N 2 0 4 _(0.11
H 2 0): C, 64.93; H, 5.21; N, 8.91. Found: C, 64.90; H, 5.10; N,
8.85.
30
EXAMPLE 32
Preparati on of N-(4-Hydroxymethylphenyl-N'-r3-(3-phenylpropionic
acid) ] urea
35
To a stirred solution of N-(4-hydroxymethylphenyl)-N'-
[3-(methyl 3-phenylpropionate) Jurea prepared as in Example 31,
(0.500 g, 1.52 mmol) in 25 mL of CH 3 0H was added 5 mL of 1 N NaOH
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and 5 mL of water. Reaction progress was monitored by HPLC. After
1.5 h, the reaction mixture was partially concentrated to remove
the CH 3 0H. The reaction mixture was then diluted with 20 mL of
water and acidified with 5 mL of 1 N HC1. A gum formed upon
5 acidification. The reaction mixture was diluted with 5 mL of
CH3OH and the reaction mixture was stirred overnight. The
resulting slurry was filtered to yield after air-drying 0.35 g
(73%) of the urea as a flocculent white powder: mp 138-140 °C; X H
NMR (DMS0-d 6 ) 8 12.3 (br s, 1 H, C00H) , 8.54 (s, 1 H, NH), 7.45-
10 7.1 (m, 9 H, Ar and Ph), 6.75 (d, J= 8.5 Hz, 1 H) , 5.11( apparent
q, 1 H), 5.01 (br s, 1 H) , 4.38 (s, 2 H), 2.85-2.65 (m, 2 H); 13 C
NMR (DMS0-d 6 ) 5 172.1, 154.4, 142.9, 139.0, 135.2, 128.4, 127.2,
127.0, 126.4, 117.4, 62.8, 50.0, 41.1; IR (KBr) cm" 1 3400, 3340,
1710, 1660, 1550, 1420, 1320, 1240. Anal. Calcd for C 17 H 18 N 2 0 4 :
15 C, 64.96; H, 5.77; N, 8.91. Found: C, 64.70; H, 5.59; N, 8.78.
EXAMPLE 33
Preparation
20 of N- ( 4-Cyanopheny 1 )-N'-[3-(3-(3' -hy dr oxy-4 ' -me thoxy phenyl )
propionic acid)]urea
A stirred suspension of 3-hydroxy-4-me thoxy benzaldehyde (15.2
g, 100 mmol) and NH 4 0Ac (15.4 g, 100 mmol) in a mixture of 45 mL
25 of EtOH and 5 mL of water was heated to 45 °C. Malonic acid (10.4
g, 100 mmol) was added as a solid and the resulting mixture was
refluxed for 19 h. The cooled reaction suspension was filtered
and the solid washed with copious amounts of EtOH to afford 12.59
g (59%) of crude product as a ivory powder. The crude product
30 (10.0 g) was slurried in hot EtOH and filtered. The solid was
air-dried to afford 8.5 g (40%) of 3-amino-3-( 3 '-hydroxyz-
ine thoxyphenyl)propionic acid as a white powder: mp 215-217 °C; ^-H
NMR (D 2 0) 5 7.1-6.9 (m, 3 H), 4.6-4.5 (m, 1 H), 3.85 (s, 3 H),
2.95-2.7 (m, 2 H); 13 C NMR (D 2 0) S 178.6, 149.3, 146.4, 130.4,
35 120.9, 115.4, 114.0, 57.2, 53.6, 41.7. Anal. Calcd for
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10
C 10 H 13 N 1 0 4 : C, 56.90; H, 6.20; N, 6.63. Found: C, 56.57, H, 6.19;
N, 6.75.
To a stirred suspension of 4-cyanophenyl isocyanate (1.44 g,
10.0 mmol) in 25 mL of CH 3 CN vas rapidly added a solution of 3-
amino-3-(3'-hydroxy-4'-methoxyphenyl)propionic acid (2.11 g, 10.0
mmol) and NaOH (0.40 g, 10 ramol) in 20 mL of 1/1 CH,CN/water.
After 17 h, the reaction mixture was partially concentrated to
remove the CH 3 CN. The reaction mixture was then diluted with 75
mL of water and washed with EtOAc (2 x 50 mL ea. ). The pH of
the reaction mixture was adjusted to 0-1 with 11 mL of 1 N HC1. A
gum formed upon acidification and the aqueous layer was decanted
from the gum and the gum washed with water. The gum was slurried
in CHC1 3 (100 mL) and stirred overnight. The resulting powder was
isolated by filtration. This solid was dissolved in EtOH (100 mL)
15 and concentrated to a thick oil. The oil was slurried in 100 mL
of refluxing CHC1 3 . The cooled suspension was filtered and the
solid air-dried to afford 2.6 g (73%) of the urea as an off-white
solid: *H NMR (DMS0-d 6 ) 5 12.3 (br s, 1 H), 9.1 (s, 1 H), 8.94
(s, 1 H), 7.64 (d, 2 H, J= 8.7 Hz), 7.54 (d, 2 H, J= 8.7 Hz),
7.0-6.7 (m, 4 H), 5.02-4.95 (m, 1 H), 3.72 (s, 3 H) , 2.8-2.6 (m,
2 H) ; 13 C NMR (DMS0 r d 6 ) 8 172.1, 153.8, 146.7, 146.3, 144.8,
135.0, 133.3, 119.5, 117.5, 117.0, 113.9, 112.4, 102.5, 55.7,
49.5, 41.0; IR (KBr) cm"i 3370, 2225, 1720, 1700, 1680, 1600,
1540, 1510. Anal. Galcd for C 18 H 17 N 3 0 5 -(0. 11 H 2 0): C, 58.60; H,
25 4.10; N, 11.39. Found: C, 58.58; H, 4.40; N, 11.32.
EXAMPLE 34
20
30
Preparation of N-(4-Cyanophenyl)-N'-(3-nonanoic acid) urea
A solution of methyl trans-2-nonenoate (3.40 g, 20.0 mmol)
and benzyl amine (2.2 mL, 2.1 g, 20 mmol) in 50 mL of MeOH was
stirred for 12 days at RT. The reaction progress was monitored by
TLC (1/1 EtOAc/hexane, UV). The reaction solution was then
35 refluxed for 1 h with no observable change by TLC. The reaction
mixture was concentrated and the crude adduct was purified by
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flash chromatography (2.5/7.5 EtOAc/hexane) to afford 4.00 g
(72%) of methyl N-benzyl 3-aminononanoate as an oil: TLC (2 .5/7 ,5
EtOAc/hexane) R f « 0.35; 1 E NMR (CDC1 3 ) 5 7.4-7.2 (m, 5 H), 3.78
(s, 2 H), 3.67 (s, 3 H), 3.03 (p f 1 H, J- 6.2 Hz), 2.46 (d, 2H,
5 J= 6.2 Hz), 1.65-1.2 (m, 10 H), 0.88 (br t, 3H); 13 C NMR (CDC1 3 )
6 173.0, 140.5, 128.3, 128.1, 126.8, 54.2, 51.5, 51.4, 51.0,
50.9, 50.8, 39.1, 34.3, 31.7, 29.3, 25.6, 22.6, 14.0.
To a solution of methyl N-benzyl 3-aminononanoate (3.50 g,
10 12.6 mmol) in 35 mL of ethanol was added 100 mg of 5% Pd/C and
the resulting suspension was treated with 50 psi of H 2 in a Parr
Type Shaker. After 3 h, 100 mg of 20% Pd(0H) 2 /C was added and the
hydrogenolysis was continued for 19 h. The reaction mixture was
then filtered through celite to remove the catalysts and
15 concentrated to afford 2.43 g (100%) of a pale yellow oil which
was a 79/21 mixture of methyl and ethyl 3-aminononanoate
respectively. Methyl ester: X H NMR (CDC1 3 ) 5 3.69 (s, 3 H) , 3.25-
3.15 (m, 1 H), 2.47 (dd, J= 4.0 Hz, 15.6 Hz, 1 H), 2.26 (dd, 1 H,
J= 9.0 Hz, 15.6 Hz), 1.6-1.2 (m, 12 H), 0.9-0.8 (m, 3 H). This
20 mixture was used directly in the next reaction.
To a stirred solution of methyl 3-aminononanoate and ethyl
3-aminononanoate (80/20, 2.00 g, 10.4 mmol) in 35 mL of ethyl
acetate was added 4-cyanophenyl isocyanate (1.50 g, 10.4 mmol) in
25 one portion as a solid. The resulting suspension was stirred for
7 h. The reaction mixture was filtered and the solid washed with
ether (50 mL) and air-dried to afford 2.91 g ( 84%) of a 79/21
mixture of the desired compounds, N-(4-cyanophenyl)-N'-[3-(methyl
nononoate) ]urea and N-(4-cyanophenyl)-N'-[3-(ethyl
30 nonanoate) ]urea as a white powder. Methyl ester: X E NMR (DMS0-
d 6 ) S 9.01 (s, 1 H), 7.68 (d, J= 8.8 Hz, 2 H, Ar), 7.58 (d, J=
8.8 Hz, 2 H, Ar), 6.36 (d, J= 8.7 Hz, 1 H), 4.05- 3.92 (m, 1 H),
3.61 (s, 3 H, C0 2 CH 3 ), 2.53-2.47 (m, 2 H, CHC0 2 ) , 1.55-1.15 (m,
10 H), 0.87 (apparent t, 3 H); 13 C NMR (DMS0-d 6 ) 6 171.5, 154.1,
35 144.9, 133.2, 119.4, 117.4, 102.3, 51.3, 46.3, 39.3, 34.1, 31.2,
28.5, 25.4, 22.0, 14.0.
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To a stirred suspension of a 79/21 mixture of N-(4-
cyanophenyl)-N'-[ 3- (methyl nonanoate) ]urea and N-(4-cyanophenyl)-
N'-[3-(ethyl nonanoate) ] urea (2.50 g, 7.52 mmol) in a mixture of
methanol (100 mL) and water (25 mL) was added 30 mL of 1 N NaOH.
The reaction progress was monitored by HPLC. The reaction was
complete after 21 h, the methanol was removed in vacuo and the
resulting slurry diluted with 150 mL of water. This slurry was
filtered and the solid was washed with water. The solid was dried
in vacuo to yield 2.07 g (81%) of the urea as a white powder: mp
>230 °C; iH NMR (DMSO-d 6 ) S 10.82 (s, 1 H) , 7.9-7.6 (m, 1 H),
7.70 (d, 2 H, J» 8.8 Hz), 7.53 (d, 2 H, J= 8.8 Hz), 3.9-3.7 (m, 1
H), 2.3-2.05 (m, 2 H) , 1.6-1.45 (m, 2 H) , 1.8 (br s, 8 H), 0.8
(apparent t, 3 H); 13 C NMR (DMS0-d 6 ) S 176.1, 154.8, 146.4,
15 132.8, 119.8, 117.3, 100.9, 34.8, 31.4, 28.9, 26.0, 22.1, 13.9.
Anal. Calcd for C 17 H 22 N 3 0 3 Na-(0. 9 H 2 0): C, 57.42; H, 6.75} N,
11.82. Found: C, 57.39} H, 6.49; N, 11.83.
10
20
30
EXAMPLE 35
Preparation of N-(4-Formylphenyl)-N'-r3-(3-(3-pyridyl) P ropionic
acid) ]urea
To a cooled (4 °C) stirred solution of 1,1'-
25 carbonyldi imidazole (3.24 g, 20.0 mmol) and imidazole (2.04 g,
30.0 mmol) in 65 mL of THF was added a solution of methyl 3-
amino-3-(3-pyridyl) propionate (3.60 g, 20.0 mmol) in 25 mL of THF
over 10 minutes. After stirring an additional 15 minutes, the
cooling bath was removed. After 45 minutes, a solution of 4-
aminobenzaldehyde (2.42 g, 20.0 mmol) in 100 mL of THF was
rapidly added to the reaction solution. The reaction mixture was
then heated to reflux for 24 h. The reaction mixture was
concentrated and the residue purified by flash chromatography
(silica gel, 6.5/93.5 CH 3 0H/ CH 2 C1 2 ) to afford 5.01 g of crude
35 product. The crude product was purified by flash chromatography
(silica gel, 0.5/9.5 CH 3 0H/ CH 2 C1 2 ) to afford 3.41 g (52X) of
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N-(4-formylphenyl)-N-[3-(methyl 3-(3-pyridyl)propionate) Jurea as
yellow foam. A small sample was recrystallized from EtOAc for
analysis, the remainder was used directly in the next reaction.
*H NMR (DMS0-d 6 ) 5 9.79 (s, 1 H), 9.16 (s, 1 H), 8.59 (s, 1 H),
5 8.46 (d, J- 3.1 Hz, 1 H), 7.9-7.7 (m, 3 H), 7.65-7.5 (m, 2 H),
7.37 (dd, J- 4.8, 7.9 Hz, 1 H), 7.12 (s, J= 8.2 Hz, 1 H), 5.25-
5.15 (m, 1 H), 3.56 (s, 3 H), 3.35-2.90 (m, 2 H); 13 C NMR (DMS0-
d 6 ) 5 191.4, 171.3, 154.4, 148.6, 147.5, 245.5, 137.3, 135.0,
131.4, 130.7, 123.9, 118.0, 52.0, 48.4, 39.8. Anal. Calcd for
10 C 17 H 17 N 3 0 4 : C, 62.38; H, 5.24; N, 12.84. Found: C, 62.01; H,
5.18; N, 12.65.
To a stirred suspension of N-(4-f ormylphenyl)-N'-[3-(methyl
3-(3-pyridyl)propionate) Jurea in 90 mL of a 5/4 mixture of MeOH
and water was added 7.60 mL of 1 N HC1 followed by 15.2 mL of 1 N
15 NaOH. After 26 h, the reaction mixture was partially concentrated
to remove the MeOH, and diluted with 50 mL of water. The reaction
solution was then washed with CH 2 C1 2 (3 x 50 mL ea.). The aqueous
layer was decolorized with Norit A and filtered through celite
and lyophilized. The residue was dissolved in 100 mL of ethanol
20 and filtered to remove the insoluble NaCl. The filtrate was
concentrated, the residue dissolved in 25 mL of water and
lyophilized. The residue was purified by reverse phase
chromatography and lyophilized to afford 1.92 g (76%) of the urea
as a vhite powder: mp 200-205 °C decomp; 1 B NMR (D 2 0) 5 9.71 (s,
25 1 H, CH0), 8.54 (s, 1 H), 8.42 (d, J= 4.9 Hz, 1 H), 7.9-7.7 (m, 3
H), 7.6-7.4 (m, 3 H), 5.14 (t, J= 7 Hz, 1 H), 2.8-2.65 (m, 2 H):
13 C NMR (D 2 0) 5 194.7, 178.3, 155.8, 147.5, 146.7, 145.4, 138.5,
135.1, 131.6, 129.9, 124.2, 118.3, 50.1, 43.7. Anal. Calcd for
C 16 H 14 N 3 0 4 Na 1 -(0.16 H 2 0): C, 56.83; H, 4.27; N, 12.43. Found: C,
30 56.80; H, 4.27; N, 12.43.
35
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EXAMPLE 36
Preparation of N-(4-Cyanophenyl)-N'-r3-(4-phenylbutanoic
acid)jurea sodium salt
5
A stirred suspension of phenylacetaldehyde (6.08 g, 50.6
mmol) and methyl (triphenylphosphoranylidene) -acetate in 150 mL
of CH3CN was heated to reflux for 1.75 h. Reaction progress was
moni-tored by TLC (1/9 EtOAc/hexane). The reaction mixture was
10 concentrated and the residue slurried in 100 mL of 0.8/9.2
EtOAc/hexane. The slurry was filtered to remove excess Wittig
reagent and triphenylphosphine oxide. The filtrate was
. .concentrated and purified by flash chromatography (80 mm id
column, silica gel, 8/92 EtOAc/hexane) to afford 7.17 g (80£) of
15 a 0.39/0.61 cis to trans mixture of methyl 4-phenylbut-2-enoate.
Trans isomer r H NMR (CDC1 3 ) 5 7.4-7.05 (m, 6 H) , 5.81 (dt, J=
1.5, 15.5 Hz, 1H), 3.69 (s, 3 H), 3.55-3.47 (m, 2 H); Cis isomer
*H NMR (CDC1 3 ) S 7.4-7.13 (m, 5 H) , 6.48 (d, J= 15.9 Hz, 1 H),
6.29 (dt, J= 7.0, 15.9 Hz, 1 H), 3.69 (s, 3 H), 3.28-3.20 (m, 2
20 H); Trans and Cis isomers 13 C NMR (CDC1 3 ) S 171.9, 166.8, 147.6,
137.6, 136.8, 133.5, 128.8, 128.7, 128.5, 127.5, 126.7, 126.3,
121.9, 121.6, 51.9, 51.4, 38.4, 38.2.
A solution of benzylamine (2.14 g, 20 mmol) and cis and trans
25 (39/61) methyl 4-phenylbut-2~enoate (3.52 g, 20.0 mmol) in 50 mL
of MeOH was stirred for 11 days at RT. The reaction was then
concentrated and purified by flash chromatography (60 mm column,
silica gel, 4/6 EtOAc/hexane) to afford 2.00 g (35%) of methyl
N-benzyl-3-amino-4-phenylbutanoate as an oil: 1 E NMR (CDC1 3 ) 5
30 7.35 (m, 10 H)i 3.80 (s, 2 H, NCH 2 ) , 3.63 (s, 3 H, C0 2 CH 3 ), 3.35-
3.22 (m, 1H), 2.87 (dd, J= 6.4, 13.5 Hz, 1 H) , 2.74 (dd, J= 7.0,
13.5 Hz, 1 H), 2.42 (d, J= 6.4 Hz, 1 H), 1.63 (br s, 1 H, NH).
To a solution of the above amine (1.80 g, 6.35 mmol) in 50 mL
35 of MeOH was added 0.18 g of 20% Pd(0H) 2 /C , The reaction mixture
was then treated with 50 psi of hydrogen in a Parr Type Shaker
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for 36 h. The reaction mixture was filtered through celite and
the filtrate concentrated to afford 1,18 g (96%) of methyl
3- amino-4~phenylbutanoate as a cloudy oil: X H NMR (CDC1 3 ) 5 7.38-
7.17 (m, 5 H), 3.68 (s, 3 H, C0 2 CH 3 ), 3.55-3.42 (m, 1 H) , 2.76
5 (dd, J= 5.7, 13.3 Hz, 1 H), 2.61 (dd, J- 8.1, 13.3 Hz, 1 H), 2.50
(dd, J= 4.1, 15.9 Hz, 1 H), 2.32 (dd, J- 8.8, 15.9 Hz, 1 H), 1.46
( br s, 2 H); 13 C NMR (CDC1 3 ) S 172.9, 138.5, 129.3, 128.6, 126.5,
51.6, 49.6, 44.0, 41.7.
10 To a stirred solution of methyl 3-amino-4-phenylbutanoate
(1.16 g, 6.00 mmol) in 25 mL of EtOAc was added 4-cyanophenyl
isocyanate (0.858 g,5.95 mmol). Solid began forming in the
reaction mixture after 30 minutes. After stirring for 16 h, the
reaction slurry was filtered to afford 0.858 g (43%) of the urea
15 as a white powder. The filtrate was concentrated and residue
slurried in ether. This slurry was filtered to afford an
additional 0.770 g (38%) of N-(4-cyanophenyl)-N' -[ 3- (methyl
4- phenylbutanoate) ]urea as a very pale yellow solid: mp 142-143.5
°C; X H NMR (DMS0-d 6 ) 5 9.03 (s, 1H, NH), 7.64 (d, J= 8.8 Hz, 2
20 H), 7.53 (d, J= 8.8 Hz, 2 H), 7.35-7.15 (m, 5 H), 6.42 (d, J= 8.5
Hz, 1 H), 4.29-4.13 (m, 1 H), 3.58 (s, 3 H, C0 2 CH 3 ), 2.9-2.73 (m,
2 H), 2.6-2.41 (m, 2 H); 13 C NMR (DMS0-d 6 ) 5 171.4, 153.9, 144.8,
138.2, 133.1, 129.1, 128.3, 126.3, 119.4, 117.4, 102.4, 51.4,
48.0, 39.9; IR (KBR) cnr 1 3340, 3320, 2220, 1740, 1673, 1596,
25 1537, 1508, 1322, 1239, 1175. Anal. Calcd for C 19 H 19 N 3 0 3 : C,
67.64; H, 5.67; N, 12.46. Found: C, 67.56; H, 5.73; N, 12.39.
To a stirred* suspension of N- ( 4-cyanophenyl ) -N' -[ 3- (methyl
4-phenylbutanoate) ] urea (1.52 g, 4.51 mmol) in 65 mL of a 4.5/2
30 mixture of methanol/water was added 4.51 mL of 1 N NaOH. After
stirring at RT for 19 h, the reaction mixture was heated to
reflux for 3.5 h. The reaction mixture was concentrated and the
residue slurried in CH 3 CN/H 2 0 (50 mL/5 mL). The resultant slurry
was filtered. The solid was dried in vacuo to afford 1.19 g (76%)
35 of the desired urea as a white powder: X E NMR (DMS0-d 6 ) 5 11.12
(br s, 1 H), 8.20 (br s, 1 H), 7.9-7.45 (m, 4 H), 7.4-7.1 (m, 5
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H), 4.1-3.9 (m, 1 H), 2.95 (dd, J= 5.9, 12.7 Hz, 1 H), 2.72 (dd,
J= 8.2, 12.7 Hz, 1 H), 2.2-2.0 (m, 2 H); NMR (DMS0-d 6 ) 8
175.5, 154.7, 146.3, 139.9, 132.7, 129.2, 127.9, 125.6, 119.8,
117.3, 100.8, 49.4, 40.6; IR (KBR) cm" 1 3440, 2226, 1687, 1592,
5 1573, 1536, 1511, 1410, 1320, 1242, 1175. Anal. Calcd for
C 19 H 19 N 3 0 3 -(1.05 H 2 0): G, 59.33; H, 5.01; N, 11.53. Found: C,
59.30; H, 4.93; N, 11.50.
EXAMPLE 37
10
Preparation of N-(4-Cyanophenyl)-N'-r3-(5-phenylpentanoic
acid)] urea sodium salt
A stirred suspension of 3-phenylpropionaldehyde (6.71 g, 50.0
15 mmol) and methyl (triphenylphosphoranylidene)-acetate (25.1 g,
75.0 mmol) in 150 mL of acetonitrile was refluxed for 1 h. The
cooled reaction mixture was concentrated. The residue was
slurried in 1/9 EtOAc/hexane (100 mL), and filtered. The filtrate
was concentrated and purified by flash chromatography (1/9
20 EtOAc/hexane, silica gel) to afford 8.41 g (88%) of methyl
5-phenylpent-2-enoate as an oil: 1 E NMR (CDC1 3 ) 8 7.35-7.13 (m, 5
H), 7.00 (dt, 1 H, J= 6.8, 15.7 Hz), 5.84 (dt, 1 H, J= 1.5, 15.7
Hz), 3.70 (s, 3 H), 2.76 (t, 2 H, J= 7.5 Hz), 2.58-2.45 (m, 2 H) ;
13 C NMR (CDC1 3 ) 5 166.9, 148.3, 140.6, 128.4, 128.2, 126.1,
25 121.3, 51.3, 34.2, 33.8.
A solution of methyl trans -5-phenylpent-2-enoate (5.71 g,
30.0 mmol) and benzylamine (3.28 mL, 30.0 mmol) in 80 mL of
methanol was stirred for 51 h. The reaction solution was
30 concentrated and the residue purified to afford 2.64 g (46%) of
starting olefin and 4.56 g (51%) of methyl N-benzyl-
3-amino-5-phenylpentanoate as a clear oil: X H NMR (CDC1 3 ) 8 7.4-
7.13 (m, 10 H), 3.78 (overlapping dd, 2 H, NCH2), 3.66 (s, 3 H,
C0 2 CH 3 ), 3.06 (m, 1 H), 2.68 (m, 2 H), 2.51 (d, 2 H, J= 6.1 Hz),
35 1.9-1.7 (m, 2 H), 1.53 (br s, 1 H); "C NMR (CDC1 3 ) 8 172.7,
142.0, 140. 4 f 128.3, 128.1, 126.9, 125.9, 53.7, 51.5, 50.8, 38.8,
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36.1, 32.0- IR (KBr) cm' 1 3080, 3040, 2950. 2860, 1730, 1500,
1460, 1440- Anal. Calcd for C 19 H 23 N 1 0 2 : C, 76.74; H, 7.80; N,
4.71. Found: C, 77.11; H, 7.93; N, 4.75.
5 To a solution of methyl N-benzyl-3-amino-5-phenylpentanoate
in 50 mL of methanol was added 100 mg of 20% Pd(0H) 2 . This
suspension was treated with 50 psi of hydrogen in a Parr Type
Shaker. After 15 h and 39 h, 100 mg of 20% Pd(0H) 2 was added.
After 63 h, the reaction mixture was filtered through celite to
10 remove the catalyst and the filtrate concentrated to afford
2.71 g (97%) of methyl 3-amino-5-phenylpentanoate as a clear oil:
X H NMR (CDC1 3 ) 8 7.35-7.14 (m, 5 h, Ph), 3.68 (s, 3 H, C0 2 CH 3 ),
3.28-3.15 (m, 1 H, CHN), 2.82-2.48 (m, 2H, CH 2 Ar), 2.50 (dd, 1
H, J = 4 Hz, 15.7 Hz), 2.31 (dd, 1 H, J= 8.8 Hz, 15.7 Hz), 1.78-
15 1.6 (m, 2 H), 1.47 (s, 2 H, NH 2 ); 13 C NMR (CDC1 3 ) 5 172.8, 141.6,
128.4, 128.3, 125.8, 51.5, 47.9, 42.5, 39.5, 32.4; IR (KBr) cm" 1
3390, 3300, 3040, 2960, 2940, 2860, 1730, 1660, 1500, 1454, 1437.
Anal. Calcd for C 12 H i7 N i°2 : c > 69.54; H, 8.27; N, 6.76. Found: C,
69.98; H, 8.08; N, 6.30.
20
To a stirred solution of methyl 3-amino-5-phenylpentanoate
(2.07 g, 9.99 mmol) in 35 mL of ethyl acetate was added 4-
cyanophenyl isocyanate (1.44 g, 9.99 mmol). After 24 h, the
reaction mixture was concentrated. The residue was slurried in 50
25 mL of ether and the slurry was filtered to afford after drying
3.01 g (86%) of the urea as an off-white powder: 1 H NMR (DMS0-d 6 )
8 9.0 (s, 1 H), 7.65 (d, 2 H, J = 8.8 Hz), 7.57 (d, 2 H, J= 8.8
Hz), 7.22 ( m, 5 H, Ph), 6.47 (d, 1 H, J=* 8.7 Hz, NH), 4.0 (m, 1
H), 3.57 (s, 3 H, CH 3 ), 2.7-2.5 (m, 4 H), 1.77 (m, 2 H)
30 contaminated with ethyl acetate; IR(RBr) cnr 1 3340, 2240, 1730,
1680, 1600, 1550, 1520, 1320, 1240.
To a stirred suspension of the above urea (2.50 g, 7.11 mmol)
in a mixture of 150 mL of methanol and 30 mL of water was added
35 28 mL of 1 N NaOH. The progress of the reaction was monitored by
HPLC. After 44 h, the reaction mixture was partially concentrated
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to remove the methanol and the residue slurried in 100 mL of
vater. The resulting slurry was filtered to afford after drying
in vacuo, 2.11 g (83£) of the product as a white solid: 1 H NHR
(DMS0-d 6 ) 5 10.93 (br s, 1 H) , 7.95 (br s, 1 H) , 7.73 (d, 2 H, J
5 = 8.4 Hz), 7.54 (d, 2 H, J= 8.4 Hz), 7.14 (m, 5 H), 3.9 (m, 1 H),
2.56 (m, 2 H), 2.23 (d, 2 H, J= 4.4 Hz), 1.7 (m, 2 H); IR(KBr)
cm" 1 3420, 3160, 3080, 3020, 2920, 2228, 1698, 1690, 1594, 1572,
1542, 15412, 1408, 1320, 1240, 1176. Anal. Calcd for
C 19 H 18 N 3 03Na-(1.32 H 2 0): C, 59.56; H, 5.43; N, 10.97. Found: C,
10 59.26; H, 5.10; N, ,11.10.
EXAMPLE 38
Preparation
15 of N-(4-Cyanophenyl)-N'-[3-(3-(4'-nitrophenyl)propionic
acid)]urea sodium salt
A stirred suspension of ammonium acetate (30.8 g, 400 mmol)
and 4-nitrobenzaldehyde (30.2 g, 200 mmol) in 50 mL of 95%
ethanol was heated to 45 °C. To the resulting thick slurry was
20 added 75 mL of 95% ethanol and malonic acid (20»8 g, 200 mmol).
The reaction mixture was heated at reflux for 24 h. The cooled
reaction mixture vas filtered and the solid washed with copious
amounts of ethanol. The solid was air-dried to afford 42.55 g of
crude product as a pale orange powder. The crude product (35 g)
25 was slurried in 300 mL of water, heated to 55 °C, and the pH
adjusted to 1 with concentrated HC1. After cooling to RT, the
slurry was filtered and the solid washed with water. The filtrate
was concentrated to approximately 250 mL and the pH adjusted to 7
with 1 N NaOH. The resulting suspension was stirred overnight and
30 then filtered. The solid was dried in vacuo to afford 4.95 g
(14%) of 3-amino-3-(4'-nitrophenyl)propionic acid as a white
powder: *H NMR (D 2 0/NaOD/TSP) S 8.15 (d, J = 8.7 Hz, 2 H) , 7.56
(d, J = 8.7 Hz, 2 H), 4.38 (t, J - 7.3 Hz, 1 H) , 2.72-2.52 (m, 2
H); 13 C NMR (D 2 0/Na0D/TSP) 5 182.2, 155.3, 149.3, 130.1, 126.6,
35 55.5, 49.5.
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To a stirred suspension of 4-cyanophenyl isocyanate (2.74 g,
19.0 mmol) in 100 mL of CH 3 CN was added a solution of 3-amino-3-
(4'-nitrophenyl)propionic acid (4.00 g, 19.0 mmol) and NaOH (0.76
g, 19 mmol) in 30 mL of water. The reaction suspension became
5 homogeneous after the addition was complete. The reaction mixture
was stirred for 6 h, then partially concentrated to remove the
CH 3 CN. A small amount of solid which had formed was removed by
filtration. The filtrate was concentrated to a thick oil and then
diluted with 50 mL of EtOH. The resulting slurry was filtered and
10 the solid washed with EtOH. The solid was dried in vacuo to
afford 2.98 g (42%) of the urea as an off-white powder: X H NMR
(D 2 0/TSP) 5 8.04 (d, J = 8.5 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H),
7.42 (d, J = 8.5 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 5.17 (t, J
= 6.9 Hz, 1 H), 2.85-2.65 (m, 2 H); i3 C NMR (D 2 0/TSP) 5 181.2,
15 158.6, 153.4, 149.3, 146.2, 136.2, 129.9, 126.7, 122.9, 121.4,
106.4, 54.7, 46.7; IR(KBr) cm" 1 3320, 2227, 1700, 1600, 1580,
1540, 1520, 1400, 1350, 1320, 1236, 1180. Anal. Calcd for
C 17 H 13 N 4 0 5 Na-(1.13 H 2 0): C, 51.45; H, 3.88; N, 14.12. Found: C,
51.32; H, 3.68; N, 13.98.
20
EXAMPLE 39
Preparation
of (S)-N-(4-Cyanophenyl)-N f -[3-(3-(3-pyridyl)propionic acid)]
25
To a stirred solution of 3-pyridinecarboxaldehyde (21.4 g,
0.20 mol) in benzene (250 mL) was added (S)-l-phenylethylamine
(24.2 g, 0.20 mol). The reaction mixture was refluxed for 2 h
with a Dean-Stark trap. The reaction mixture was then allowed to
30 cool to room temperature and concentrated. Purification of the
residue by distillation afforded 40. 8g (97 %) of
N-[ (S)-l-phenyethyl)]pyridine-3-carboxaldimine (1) : B.p. 123
°C/0.25 Torr; 1 E NMR (300 MHz, CDC1 3 ) 5 1.59 (d, J = 6.6 Hz, 3H),
4.55 (q, J = 6.6 Hz, 1H), 7.21-7.43 (m, 6H), 8.14 (d, J » 7.9 Hz,
35 1H), 8.37 (s, 1H), 8.62 (d, J = 3.4 Hz, 1H), 8.7 (s, 1H). 13 C
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10
NMR (75.5 MHz, CDC1 3 ) 5 156.3, 151.3, 150.2, 144.6, 134.5, 131.7,
125.4, 126.9, 126.4, 123.4, 69.9, 24.7.
A stirred suspension of 32.7 g (5 equiv) of activated zinc
dust in 300 mL of THF vas heated to reflux under N 2 . Several
O.lmL portions of methyl bromoacetate were added with vigorous
stirring to initiate the reaction. When a green color appeared,
21.0 g (0.100 mol) of N-[(S)-l-phenyethyl)]pyridine-3-
carhoxaldimine in 100 mL of THF vas added. Then 37.9 mL (4
equiv) of methyl bromoacetate vas added dropvise over 45 min to
the refluxing mixture. The mixture vas refluxed for an
additional 10 min, cooled to room temperature, diluted with 500
mL of THF, and the reaction quenched vith 140 mL of 50% aqueous
K 2 C0 3 . Rapid stirring for 45 min gave a suspension. The THF
15 layer vas decanted, and the residue vas rinsed vith THF. The
combined THF layers vere concentrated and the resulting crude oil
dissolved in ethyl acetate. The reaction mixture vas then vashed
vith vater and brine, dried (MgS0 4 ) and concentrated to afford
23.2 g (92 %) of a mixture of diastereomers (1:1) of the ^-lactam
20 <4S) and (4R) [(S)-N-phenyethyll-3-amino-3-(3-pyridyl)propionate
and e-(phenylethylamine)-(3-pyridyl)methylpropionate.
The product obtained from the above reaction vas dissolved in
200 mL of 6N HC1. The reaction mixture vas refluxed for 15 min,
25 cooled to room temperature, partially concentrated and the pH
adjusted to 4-5 vith basic resin. The reaction mixture vas
filtered, and concentrated. The residue vas dissolved in
methanol, dried over MgS0 4 § filtered and concentrated to afford
an oil consisting of a mixture of the diastereomers,
N-(S)-phenyethyl-3-(R,S)-amino-3-(3-pyridyl)propionic acid.
30
To the residue (24.8 g) obtained by the above procedure vas
added 19.8 g (0.24 mol) of benzyl alcohol in 200 mL of methylene
chloride and 1.0 g of DMAP. The reaction mixture vas cooled to 0
35 °C and 37.7 g (0.18 mol) of DCC in 100 mL of methylene chloride
vas added. The mixture vas alloved to warm to room temperature
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and stirred an additional 12 h. The reaction mixture was then
filtered to remove the DCU and washed with water, brine, and
dried (MgS0 4 ). After silica chromatography (elution with 1:1
hexane-ethyl acetate), 3.91 g (12%) of benzyl
5 N-[ (S)-phenyethyl3-3-(S)-amino-3-(3-pyridyl)propionate was
isolated from the mixture of diastereomers as an oil. R £ = 0.32
(ethyl acetate); X H NMR (300 MHz, CDC1 3 ) S 1.25 (d, J . 6.7 Hz,
3H), 2.20 (bs, 1H), 2.65 (ddd, J = 15.4, 9.0, 5.1 Hz, 2H), 3.40
(q, J = 6.7 Hz, 1H), 3.80 (dd, J = 8.9, 5.1 Hz, 1H), 5.10 (dd, J
10 = 27.0, 12.2 Hz, 2H), 7.10 (d, J = 6.4 Hz, 2H), 7.23-7.47 (m,
9H), 7.56 (d, J = 7.8 Hz, 1H), 8.40 (s, 1H), 8.52 (d, J = 4.8 Hz,
1H); 13 C NMR (75.5 MHz, CDC1 3 ) 5 170.9, 149.2, 149.0, 144.5,
137.7, 135.5, 134.7, 128.5, 125.3, 127.0, 126.5, 123.5, 66.4,
55.0, 54.2, 42.9, 24.9.
15
To a stirred suspension of 3.0 g of the same amino ester and
an equal weight of 10% Pd/C in dry methanol (50 mL) , was added
anhydrous ammonium formate (5.2 g, 83 mmol) in a single portion
under nitrogen. The resulting reaction mixture was stirred at
20 reflux for 6 h and then the catalyst was removed by filtration
through a celite pad. The reaction mixture was concentrated and
refluxed in methanol (30 mL) while 30 mL of ethyl acetate was
slowly added over 15 min. The slurry was allowed to cool to room
temperature, and filtered to afford 457 mg of the fj-amino acid,
25 (S)-3-amino-3-(3-pyridyl)propionic acid. The residue from the
filtrate was resubmitted to the above conditions to yield another
210 mg of the (3-amino acid, (S)-3-amino-3-(3-pyridyl)propionic
acid. The total yield was 667 mg (48X) of the amino acid. X H
NMR (300 MHz, D 2 0) S 2.98 (dq, J » 18.2, 6.9 Hz, 2H), 4.73 (t, J
30 = 7.3 Hz, 1H), 7.52 (dd, J = 17.5, 5.0 Hz, 1H), 7.96 (d, J = 8.0
Hz, 1H), 8.55 (d, J m 20 Hz, 1H), 8.59 (s, 1H); 13 C NMR (75.5
MHz, CDC1 3 ) 5 176.6, 149.5, 147.7, 136.3, 132.6, 124.9, 50.5,
40.0.
35 To a solution of sodium hydroxide (120 mg, 3 mmol) and 498 mg
(3.4 mmol) of (S)-3-amino-3-(3-pyridyl)propionic acid in methanol
WO 90/02112
-54-
PCT/US89/03616
10
(45 mL) was rapidly added a solution of p-cyanophenyl isocyanate
in methyl acetate (65 mL). The temperature of the reaction
mixture dropped 2-5 °C after the addition. The reaction mixture
was then stirred for 15 min and concentrated. The residue was
dissolved in methanol (5 mL) and ethyl acetate (5 mL) and
refluxed until the solution becomes turbid (2-5 min). To this
mixture was added ethyl acetate (45 mL) slowly, and the heating
was stopped halfway through the addition. The mixture was
allowed to cool slowly to 45 °C, at which time the solid was
filtered off. The/solid was washed with ethyl acetate (2 X 2.5
mL) and dried to afford 900 mg (90£) of the product as a white
solid. [a]* 6 = 59.5° (c 5.12, H 2 0). iH NMR (300 MHz, D 2 0) 6
2.69 (dd, J = 7.2, 1.8 Hz, 2H) , 5.09 (t, J = 6.4 Hz, 1H) , 7.26
(d, J = 8.8 Hz, 2H), 7.39 (dd, J = 7.9, 4.9 Hz, 1H), 7.45 (d, J =
15 8.8 Hz, 2H), 7.81 (dt, J = 8.0, 1.5 Hz, 1H), 8.36 (dd, J = 4.9,
1.2 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H). 13 C NMR (755 MHZ) D ^ Q) §
178.5, 156.0, 147.6, 146.8, 143.3, 138.6, 135.2, 133.4, 124.3,
120.1, 118.8, 103.8, 50.2, 43.8. Anal. Calcd for C 16 H 13 N 4 Na0 3 -
6H 2 0 (343.10) 5 C 56.01, H 4.17, N 16.03; found: C 56.10 , H
20 4.08, N 16.14.
EXAMPLE 40
25
Conversio n of (S)-N-(4-Cyanophen y l)-N'-r3-(3-(3-pvrid y l)proD ionic
acid)]urea to (S)-N-(4-Carbamoylphenyl)-H' > -r3-(3-(3-pvridy lV
propionic acid urea sodium salt
30
35
Hydrogen peroxide (302T, 0.3 mL, 2.64 mmol) was added to a
stirred suspension of
(S)-N-(4-Cyanophenyl)-N'-[3-(3-(3-pyridyl)propionic acid)]urea
(0.250 g, 0.753 mmol) in ethanol (1 mL), water (1 mL) and sodium
hydroxide (6N, 0.2 mL, 1.20 mmol). The reaction mixture was
stirred for 25 min at room temperature until the contents of the
flask became clear and the evolution of gas (oxygen) stopped.
Sodium bisulfite (0.2 g) was added to the reaction mixture to
destroy excess hydrogen peroxide. The reaction mixture was
WO 90/02112 PCT/US89/03616
-55-
concentrated in vacuo at room temperature and then
chromatrographed (PRP-1 column HPLC, 2% acetonitrile in vater as
the eluant). Pure fractions were combined and lyophilized to
afford 0.20 g (76%) of the desired product as a vhite crystalline
5 powder. 1 E NMR (D 2 0) d 2-72 (d, 2H, J=7.0 Hz), 5.13 (t, 1H,
J=7.0 Hz), 7.37 and 7.73 <AB quartet, 4H, J=7.1 Hz), 7.42-7.48
(m, 1H), 7.88 (d, 1H, J=7.7 Hz), 8.43 (m 1H), 8.53 (m, 1H).
EXAMPLE 41
10
Preparation of (S)-N-(4-Cyanophenyl)-N' -[ 3-(3-phenylpropionic
acid) ]urea
(S)-3-amino-3-phenylpropionic acid hydrochloride was
15 separated from commercially available 3-amino-3-phenylpropionic
acid hydrochloride (Aldrich) by the method of Fisher, Scheibler,
and Groh as it appears in "Chem. Ber.", Vol. 43 pages 2020-3-
(1910). The compound, 1.08 grams, was a single peak by HPLC
(chiral); [tx]D 20 + 2.36, 3-0% in MeOH; lit. [<x]24D + 3.3o, 2. 95%
20 in MeOH. Anal. Calcd for C 9 H 1 1 N0 2 -HC1(H 2 0) 0 m 13L : C, 53.08; H,
6.05; N, 6.88. Found: C, 53.06; H,6.04; N, 6.82.
To a stirred suspension of (S)-3-amino-3-phenylpropionic acid
hydrochloride (1.00 g, 6.05 mmol) and 4-cyanophenyl isocyanate
25 (1.0 g, 6.9 mmol) in 50 mL of acetonitrile was added 13 mmol of 1
N NaOH. The clear solution which immediately formed was stirred
overnight before the solvents were removed at reduced pressure.
The residue was dissolved in 100 mL of water and washed with
ethyl acetate (2 x 50 mL)* The aqueous layer was acidified to a
30 pH of 2 with concentrated HC1 to produce a gummy solid. The gum
yielded, after thorough drying in a vacuum oven, 1.20 grams (64%)
of the desired product, as a brittle white solid. The product
showed one peak on HPLC using a Daicel Chiral pak VH column; IR
(KBr) cm" 1 3360, 2220, 1710, 1670, 1590, 1540, 1410, 1320, 1240,
35 1180; 1H NMR (DMS0-d 6 ) d 9.2 (s, 1H) , 7.7 (d, 2H, J=8.7Hz), 7.6
(d, 2H, J=8.7Hz), 7.3 (m, 5H), 7.1 (d, 1H, J=8.7Hz), 5.2 (q, 1H),
WO 90/02112
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PCT/US89/03616
2,8 (m, 2H); [ajD 21 -3.45° , 5.0% in MeOH. Anal. Calcd for
C X 7 H i5 N 30 3 -0*20)0 5 ; c, 64.29; H, 5.05; N, 13.23. Found C,
64.28; H, 5.08; N, 12.96.
5 EXAMPLE 42
Preparation of
N-[5-(2-Cyanopyridyl)]-N y -[3-(3-(3-pyridyl)propionic acid)]urea
Sodium salt
10
A solution of 2-cyano-5-pyridylcarbonylazide (4.05 g, 23.3
mmol) in 100 mL of dried toluene was heated at 80°C for three
hours. To this cooled solution was added 4.23 g (22.4 mmol) of
3-amino-3-phenylpropionic acid sodium salt and the slurry stired
15 overnight at room temperature. The solvent was removed at
reduced pressure and the residue chromatographed using a water
mobile phase on a PRP-1 preparative column. The desired
fractions were combined and lyophilized to give 1.4 grams (18%)
of a white fluffy powder: IR (KBr) cm* 1 3400, 2230, 1700, 1580,
20 1560, 1400, 1240; *H NMR (D 2 0) S 8.5 (m, 3H), 7.9 (m, 2H)/7.7
(d, 1H, J=8.7Hz), 7.45 (m, X H), 5.2 (m, 1H), 2.8 (m, 2H): 13 C NMR
(D 2 0) S 181.2, 158.5, 150.5, 149.6, 143.9, 142.6, 141.2, 138.0,
132.8, 128.6, 127.1, 127.0, 120.4, 53.1, 46.5.
25 EXAMPLE 43
Preparation of N-[5-(2-Cyanopyridyl) 1-N f -[3-(3-phenylpropionic
acid) ] urea
30 To a solution of 3-amino-3-phenylprop ionic acid (2.00 g, 12.0
mmol) in 24 mL 0.5 N NaOH was added a solution of
2-cyano-5-pyridyl isocyanate (2.03 g, 13.9 mmol) in 20 mL of
acetonitrile: acetone. The reaction mixture was stirred overnight
and then the solvents removed at reduced pressure on a RotoVac.
35 The residue ws dissolved in 150 of equal parts of water and
dichlorome thane. The aqueous layer was extraced with
WO 90/02112
-57-
PCT/US89/03616
dichlorome thane (2 x 50 mL) and acidified to a pH of 2-3 with
dilute HC1. The gummy precipitate was stirred overnight and the
desired product isolated by filtration to yield 1.4 g (37%) of a
white powder: mp 103-107°C; IR (KBr) cm" 1 3350, 2233, 1700, 1680,
5 1540, 1235; *H NMR (DMS0-d 6 ) 6 9-4 (s, 1H), 8.6 (m, 1H), 8.1 (m,
1H), 7.9 (m, 1H), 7.2-7.4 (m, 6H), 5.2 (q, 1H) , 2.8 (m, 2H); "C
NMR (DMS0-d6) 5 172.3, 154.3, 143.5, 142.3, 142.0, 131.2, 130.1,
128.9, 127.9, 125.4, 119.6, 53.2, 51.8.
10 EXAMPLE 44
Preparation of N-(6-Indazolyl)-N' -[3-(3-phenylpropionic
acid)urea) ]
15 To a stirred solution of l,l'-carbonyldiimidazole (1.82 g,
11.2 mmol) and imidazole (1.14 g, 16.8 mmol) in 30 mL of THF at
RT was added a solution of methyl 3-phenylpropionate (2.00 g,
11.2 mmol) in 10 mL of THF over 20 minutes. Then, a suspension of
6-aminoindazole (1.49 g, 11.2 mmol) in 20 mL of THF was rapidly
20 added. After 1 h, the reaction mixture was refluxed for 16 h. The
reaction mixture was then concentrated. The residue was purified
by flash chromatography (silica gel, 4/96
methanol/dichloromethane) to yield a slightly impure sample of
N-(6-indazolyl)-N'-[3-(methyl 3-phenylpropionate) ]urea. This
25 sample was purified by flash chromatography (silica gel, 16/84
ethyl acetate/dichloromethane) to afford 0.86 g (23%) of the
desired ester which was used in the next reaction.
To a stirred solution of N-(6-Indazolyl)-N'-[3-(methyl
30 3-phenylpropionate) ]urea(0. 800 g, 2.36 mmol) in 8 mL of methanol
was added 2.36 mL of 1 N NaOH(aq). After 71 h, the reaction
solution was partially concentrated to remove the methanol and
diluted to a volume of 25 mL with water. The resulting slurry was
washed with ethyl acetate (2 x 25 mL ea.). The aqueous layer was
35 partially concentrated to remove traces of ethyl acetate and then
acidified with 3.0 mL of 1 N HC1 followed by the addition of 0.5
WO 90/02112
-58-
PCT/US89/03616
g of NaOH. A gum formed which solidified on stirring. The slurry
was filtered and the solid dried to afford 0.56 g (73%) of the
urea: *H NMR (DMS0-d 6 ) 5 12.35 (br s, 1 H), 8.68 (d, 1 H, J= 8.9
Hz), 2.68 (dd, 1 H); "C NMR (DMS0-d 6 ) S 172.1, 151.9, 150.4,
5 142.4, 141.1, 137.7, 128.3, 121.5, 116.6, 113.4, 95.3, 50.4.
EXAMPLE 45
N- [ 5- ( 2-Carbamoylpy ridy 1 ) ] -N ' - f 3- ( 3- ( 3-py r idy 1 ) prop ioni c
10 acid)]urea Sodium , Salt
To a stirred solution of N-[5-(2-cyanopyridyl) J-N'-[3-(3-
(3-pyridyl)propionic acid)Jurea sodium salt (108 mg, 0.32 mmol)
in 3 mL of 1:1 ethanol/water were added 0.1 mL of 6 N NaOH (0.6
15 mmol) and 0.15 mL of 30% hydrogen peroxide. The reaction was
stirred for thirty minutes at room temperature at which time 0.3
g of sodium bisulfite was added to quench the reaction. The
solvents were removed at reduced pressure and the residue
chroma tographed on a PRP-1 preparative chromatography column. The
20 desired fractions were combined and lyophilized to give 30 mg of
the desired urea as a white solid; IR (KBr) cm" 1 3400, 1680,
1580, 1550, 1400, 1240: *H NMR (D 2 0) 8 8.4 (s, 1H), 8.3 (s, 2H),
7.8-7.6 (m, 3H), 7.3 (m, 1H), 5.6 (t, 1H, J=7.3Hz), 2.6 (d, 2H,
J=7.3Hz); 13 C NMR (D 2 0) 5 182.2, 173.0, 159.8, 151.3, 150.5,
25 145.9, 143.2, 142.7, 142.3, 139.0, 130.2, 128.1, 127.1, 54.0,
47.6.
EXAMPLE 46
30 N-[5-(2-Carbamoylpyridyl) l-N^ -[3-(3-phenylpropionic acid) lurea
Sodium Salt
To a stirred suspension of N-[5-(2-cyanopyridyl) ]-N' -[methyl
3-(3-phenylpropionate)]urea (108. mg, 0.33 mmol) in 3 mL of 1:1
35 ethanol/water were added 0.15 mL of 6 N NaOH (0.90 mmol) and 0.15
mL of 30% hydrogen peroxide. The reaction was stirred for 30
WO 90/02112
-59-
PCT/US89/03616
10
15
20
25
30
minutes at room temperature at which time 0.3 g of sodium
bisulfite was added to quench the reaction. The solvents were
removed at reduced presssure and the residue chroma tographed on a
PRP-1 preparative chromatography column. The desired fractions
were combined and lyophilized to give 90 mg (78%) of the desire
urea as a fluffy white powder? IR (KBr) cm -1 3320, 1680, 1580,
1560, 1560, 1410, 1240: *H NMR (DMS0-d 6 ) & 11.6 (s, 1H), 9.25 (s,
1H), 8.75 (s, 1H), 8.1 (d, 1H, J=9Hz), 7.9 (s, 1H) , 7.8 (d, 1H,
J=9Hz), 7.4-7.1 (m, 6H), 5.1 (m, 1H), 2.4 (m, 2H); 13 C NMR
(DMSO-dg) 6 175.5, 166.4, 155.2, 146.1, 141.7, 141.1, 137.9,
128.0, 126.1, 123.6, 122.1, 52.24, 46.0.
R2R3
R 1 -N- U - N-^T^COOH
R 4 R 5
35
5i
2i
?3
5±
Ex.
1
4-Ethoxycarbonylphenyl
0
3-Phenyl
H
H
H
Ex.
2
4-Ace tylpheny 1
0
3-Phenyl
H
H
H
Ex.
3
4-Bromophenyl
0
3-Phenyl
H
H
H
Ex.
4
4-Cyanophenyl
0
3-Phenyl
H
H
H
Ex.
5
4-Cyanophenyl
0
3-Pyridyl
H
H
H
Ex.
6
4-Ni trophenyl
0
3-Phenyl
H
H
H
Ex.
7
4-Carbomoylphenyl
0
3-Phenyl
H
H
H
Ex.
8
4-Sulfamylphenyl
0
3-Phenyl
H
H
H
Ex.
9
4-Car borne thoxylpheny 1
0
3-Phenyl
H
H
H
Ex.
10
4-Car boe thoxyphenyl
0
3-Pyridyl
H
H
H
Ex.
11
4-Carbamoylphenyl
0
3-Pyridyl
H
H
H
Ex.
12
4-Carboxyphenyl
0
3-Pyridyl
H
H
H
Ex.
13
4-Iodophenyl
0
3-Phenyl
H
H
H
Ex.
14
4-Chlororphenyl
0
3-Phenyl
H
H
H
Ex.
15
3-Chlorophenyl
0
3-Phenyl
H
H
H
Ex.
16
4-Methylphenyl
0
3-Phenyl
H
H
H
Ex.
17
4-Trif luorophenyl
0
3-Phenyl
H
H
H
Ex.
18
4-Cyanophenyl
0
4-Me thoxyphenyl
H
H
H
Ex.
19
4-Cyanophenyl
0
2-Naphthyl
H
H
H
WO 90/02112
-60-
PCT/US89/03616
— - mm
Ex.
20
4-Cyanophenyl
0
3, 4-Dimethoxy-
phenyl
H
H
H
Ex.
21
4-Cyanophenyl
0
3,4-Methylene-
dioxyphenyl
H
H
H
D
£iX •
4-Cyanophenyl
0
1-cyclooctyl
H
H
H
Ex .
23
4-Cyanophenyl
S
3-Phenyl
H
H
H
Ex,
24
4-Cyanophenyl
0
3-Quinolyl
H
fi
H
Ex,
25
4-Methoxycarbonylphenyl
S
3-Phenyl
H
H
H
Ex.
26
4- Cy ano phenyl
0
3-Cyclohexyl
H
H
H
1 A
ethyl
Ex*
27
4-Cyanophenyl
0
3-Ni trophenyl
H
H
H
Ex.
28
4-Cyanophenyl
0
4-Pyridyl
H
H
H
Ex.
29
4-Carboxyphenyl
0
3-Phenyl
H
H
H
Ex.
30
Phenyl
0
3-Phenyl
H
H
H
1 Q
13
Ex.
31
4-Formylphenyl
0
3-Phenyl
H
H
H
EX.
32
*
4-Hydroxyphenyl
0
3-Phenyl
H
H
H
EX.
33
4-Cy ano phenyl
0
3'-Hydroxy-4'-
methoxyphenyl
H
H
H
Ex.
34
4-Cyanophenyl
0
Hexyl
H
H
H
on
bx.
35
4-Formylphenyl
0
3-Pyridyl
H
H
H
JDX •
36
4-Cyanophenyl
0
Benzyl
H
H
H
Ex .
37
4-Cyanophenyl
0
Phenyethyl
H
H
H
Ex.
38
4-Cyanophenyl
0
4-Ni trophenyl
H
H
H
Ex.
39
§ Aft V ^
4-Cy ano phenyl
0
(S)-3 Pyridyl
H
H
H
25
Ex.
40
4-Carbamoyl
0
(S)-3 Pyridyl
H
H
H
Ex .
41
4-Cyanophenyl
0
(S) -3-Phenyl
H
H
H
Ex.
42
5-(2-Cyanopyridyl)
0
3-Pyridyl
H
H
H
Ex.
43
5-(2-Cyanopyridyl)
0
3-Phenyl
H
H
H
Ex.
44
6-Indazolyl
0
3-Phenyl
H
H
H
30
Ex.
45
5- (2 -Carbamoyl pyridyl)
0
3-Phenyl
H
H
H
Ex.
46
5- ( 2 -Carbamoy Ipy r i dy 1 )
0
3-Phenyl
H
H
H
35
PCT/US89/03616
-61-
WE CLAIM:
A compound corresponding to the formula
*1 "
COOH
wherein X 1 is 0 or S, wherein R t is an optionally
substituted cyclic, optionally substituted heterocyclic
including optionally substituted heteroaromatic,
optionally substituted bicyclic including optionally
substituted aromatic bicyclic, or optionally substituted
phenyl, said phenyl corresponding to
wherein X 2 , X 3 , X 4 , X 5 and X 6 are the same or different
and are selected from the group consisting of:
H,
CF 3 ,
CF 2 CF 3 ,
CH 2 GF 3 ,
C x -C 4 alkyl,
CH=NOCH 3 ,
CH=NOH ,
CHO,
CH 2 OCH 3 ,
CH 2 0H,
CN,
COCF 3 ,
COC^-Cg alkyl,
WO 90/02112
-62-
PCI7US89/03616
10
C0NH 2 ,
CONHCi-C^ alkyl,
CONCCi-Cg alkyl) 2 ,
COOCi^ alkyl,
COOH,
NH 2 ,
NHCj -C 3 alkyl,
N^-C^ alkyl) 2 ,
NHCHO ,
CI, with fhe proviso that X 3 and X 5 may not both
be CI,
Br,
I,
F,
15 NHCOCH3 »
NHC0NH 2 ,
NHS0 2 CH 3 ,
C 1 -C 3 alkyl COOH,
N0 2 ,
OCi-Cj alkyl, with the proviso that X 4 may not be
0CH 2 CH 3
OCOCH3 ,
OH,
S^-Cs alkyl,
25 SOCi-Ca alkyl,
S0 2 C 1 -C 3 alkyl,
S0 2 NH 2 ,
S0 2 NHC 1 -C 3 alkyl,
SO^C^-^ alkyl) 2 ,
30 S0 3 H,
and where substituents at any two of X 2 , X 3 , X 4 ,
X 5 or X 6 form a fused ring,
wherein R 2 , R 3 , R 4 , and R 5 are the same or different and are
selected from the group consisting of
35 H,
optionally substituted straight chain or branched
20
-63-
PCT/US89/03616
C x -C 10 alkyl,
optionally substituted cyclic C 3 -C 10 alkyl,
optionally substituted cyclic,
optionally substituted heterocyclic including
optionally substituted heteroaromatics,
optionally substituted bicyclic including optionally
substitute aromatic bicyclic, or
optionally substituted phenyl, and
enantiomers and physiologically acceptable salts thereof vith
the proviso that if X 4 is N0 2 or CN, at least one of the
group R 2 , R 3 , R 4 , and R 5 is not H, and if one of the group
R 2» R 3 f R 4 anc * R5 is CH 3 , at least one of the remaining
groups is not H.
The compound of claim 1 wherein R x is selected from the group
consisting of optionally substituted phenyl, optionally
substituted pyridyl, optionally substituted pyrimidyl,
2-indanyl, or 6-indazolyl.
The compound of claim 2 wherein R 2 is an optionally
substituted phenyl wherein X 4 is selected from the group
consisting of CN, N0 2 , C0 2 CH 3 , CONH 2 , HCO, S0 2 NH 2 , CH 3 S0 2 ,
and C0 2 C 2 H 5 .
The compound of claim 2 wherein R x is an optionally
substituted pyridyl.
The compound of claim 2 wherein R x is an optionally
substituted pyrimidyl.
The compound of claim 1 wherein R 2 is selected from the group
consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
quinolyl, or isoquinolyl.
The compound of claim 1 wherein X, is 0.
WO 90/02112 PCT/US89/03616
-64-
10
15
20
8. The compound of claim 1 having the formula:
0 R, R.
It \ / 3
N - C - N - C - C - C00H
1 1 /N
X 6 H n K R 5
9. The compound of claim 8 wherein X 2 , X 3 , X 5 and X e are H and
X 4 is selected from the group consisting of CN, N0 2 , C0 2 C 2 H 5 ,
C0 2 CH 3 , C0NH 2 , CI, Br, F, I, HCO, CH 3 C0, S0 2 NH 2 and CH 3 S0 2 .
10. The compound of claim 8 wherein R 3 , R 4 and R 5 are H and R 2 is
selected from the group consisting of phenyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, naphthyl, quinolyl, and
( CH 2)i-6 cycloalkyl (C 3 -C 8 ).
11. The compound of claim 9 wherein X 4 is selected from the group
consisting of CN, N0 2 , C0NH 2 , CH0, C0 2 CH 3 and C0 2 C 2 H 5 .
12. The compound of claim 11 wherein R 2 is selected from the
group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl .
13. The compound of claim 11 wherein X 2 , X 3 , X 5 and X 6 are H, X 4
is selected from the group consisting of CN, N0 2 , C0NH 2 , HCO,
25 C0 2 C 2 H 5 , C0 2 CH 3 , CI, Br, F, I, CH 3 C0, CH 3 S0 2 , and S0 2 NH 2 , R 3 ,
R 4 and R 5 are H, and R 2 is selected from the group consisting
of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, naphthyl,
quinolyl and (CH 2 ) l _ 6 cycloalkyl (C 3 -C 8 ).
30 14. The compound of claim 13 wherein X 4 is CN and R 2 is
3- pyridyl.
15. The compound of claim 13 wherein X 4 is CN and R 2 is phenyl.
35 16. The compound of claim 13 wherein X 4 is CN and R 2 is
4- pyridyl.
WO 90/02112
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PCT/US89/03616
17. The compound of claim 13 wherein X 4 is N0 2 and R 2 is phenyl.
18. The compound of claim 13 wherein X 4 is C0 2 C 2 H 5 and R 2 is
5 phenyl .
19. The compound of claim 13 wherein X 4 is CN and R, is CH -
cyclohexyl .
10 20. The compound of claim 4 vherein R 3 , R 4 and R 5 are H and R-, is
selected from the group consisting of phenyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, naphthyl, quinolyl, and (CH 2 ) 1 _ 6
cycloalkyl (C 3 -C 8 ).
15 21. The compound of claim 5 wherein R 3 , R 4 and R 5 are H and R 2 is
selected from the group consisting of phenyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, naphthyl, quinolyl, and (CE 2 ) 1 , 6
cycloalkyl (C 3 -C 8 ).
20 22. The compound of claim 13 wherein X 4 is C0NH 2 and R, is
3-pyr idy 1 .
25
30
23. The compound of claim 13 wherein X 4 is CH0 and R 2 is
3- pyridyl.
24. The compound of claim 13 wherein X 4 is C0NH 2 and R 2 is
phenyl .
25. The compound of claim 13 wherein X 4 is CHO and R 2 is phenyl
26. The compound of claim 13 wherein X 4 is C0NH-, and R, is
4- pyridyl.
35
27. The compound of claim 13 wherein X 4 is CHO and R 2 is
4-pyridyl.
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PCT/US89/03616
28. The compound of claim 20 wherein R x is 5-(2-cyanopyridyl) and
R 2 is 3-pyridyl.
29. The compound of claim 20 wherein R x is 5-(2-cyanopyridyl) and
5 R 2 is phenyl*
30. The compound of claim 1 wherein the compound is selected from
the group of physiologically acceptable salts comprising
hydrochloride, phosphate, citrate, sulfate, bisulfate,
10 sodium, potassium, ammonium, calcium, malate, tosylate,
benzoate and magnesium salts*
31- A process for sweetening edible products comprising foods,
beverages, confections, chewing gums, pharmaceuticals,
15 veterinary preparations and toilet, cosmetic and hygiene
products characterized in that an effective sweetening amount
of a compound of claim 1 is added to said edible products.
32. Edible products sweetened according to the process of
20 claim 31.
33. Sweetening compositions characterized in that said
compositions comprise an effective sweetening amount of a
compound of claim 1 and a physiologically acceptable carrier
25 therefor.
34. The sweetening compositions of claim 33 wherein the carrier
is a bulking agent.
30 35* The sweetening compositions of claim 33 wherein the carrier
is selected from the group consisting of water, polymeric
dextrose, starch and modified starches, maltodextrins ,
cellulose , methylcellulose , cellobii tol ,
carboxymethylcellulose, maltitol, hydroxypropylcellulose ,
35 hemicelluloses, microcrystalline cellulose, other cellulose
derivatives, sodium alginate, pectins and other gums,
WO 90/02112
-67-
PCT/US89/03616
lactose, maltose, glucose, leucine, glycerol, mannitol,
sorbitol, sodium bicarbonate, and phosphoric, citric,
tartaric, fumaric, benzoic, sorbic, and propionic acids and
their sodium, potassium and calcium salts and mixtures of any
5 of the above.
36. A sweetening composition comprising:
(a) a first sweetening agent comprising a compound of
claim 1; and
10
(b) a second sweetening agent which is not a compound of
claim 1.
37. The sweetening composition of claim 36 further comprising a
15 bulking agent.
38. The sweetening composition of claim 36 wherein said second
sweetening agent is selected from the group consisting of
sucrose, corn syrups, fructose, aspartame, alitame,
20 neohesperidin dihydrochalcone, high fructose corn syrup,
hydrogenated isomaltulose, stevioside type sweeteners,
L-sugars, lactitol, neosugar, glycyrrhizin, xylitol,
acesulfam-K, sodium saccharin, potassium saccharin, calcium
saccharin, cyclamic acid and the sodium, potassium, and
25 calcium salts thereof, sucralose, monellin, thaumatin and
mixtures thereof.
39. A process comprising
(a) reacting a compound of the formula:
30
with a compound of the formula
\ /
35 H 2 N - C - a - C00H
R 4 R 5
-68-
PCT/US89/03616
wherein X 1 is 0 or S, wherein R x is an optionally
substituted cyclic, optionally substituted heterocyclic
including optionally substituted heteroaromatic,
optionally substituted bicyclic including optionally
substituted aromatic bicyclic, or optionally
substituted phenyl, said phenyl corresponding to:
x r — & 6
wherein X 2 , X 3 , X 4 , X 5 and X 6 are the same or different and
are selected from the group consisting of:
H,
CF 3 ,
CF 2 CF 3 ,.
CH 2 CF 3 ,
C!-^ alkyl,
CH=NOCH 3 ,
CI, with the proviso that X 3 and X 5 may not both
be CI,
Br,
I,
F,
CHO,
CH 2 0CH 3 ,
CN,
COCF 3 ,
CO^-^ alkyl,
C0NH 2 ,
C0NHC 1 -C 3 alkyl,
CONCCi^ alkyl) 2 ,
COOCj^-Ca alkyl,
NHCj-Cg alkyl,
NCCi-Ca alkyl) 2 ,
NHCHO,
WO 90/02112
-69-
PCT/US89/03616
NHCOCH3 ,
NHS0 2 CH 3 ,
C x -C 3 alkyl C00H,
N0 2 ,
5 OCi-Cg alkyl, with the proviso that X 4 may not be 0CH 2 CH 3
OCOCH3 ,
SC 1 -C 3 alkyl,
SOC^-Cj alkyl,
SO^-C^ alkyl,
10 S0 2 NH 2 ,
S0 2 NHC 1 -C 3 alkyl,
S0 2 N(C 1 -C 3 alkyl) 2 ,
S0 3 H,
and where substituents at any two of X 2 , X 3 , X 4 , X 5 or X 6
15 form a fused ring, and
wherein R 2 , R 3 , R 4 , and R 5 are the same or different and are
selected from the group consisting of
H,
20 optionally substituted straight chain or branched
C x -C 10 alkyl,
optionally substituted cyclic C 3 -C 10 alkyl, optionally
substituted cyclic,
optionally substituted heterocyclic including optionally
25 substituted heteroaromatics , optionally
substituted bicyclic including optionally
substituted aromatic bicyclic, or optionally
substituted phenyl, and enantiomers and
physiologically acceptable salts thereof with the
30 proviso that if X 4 is N0 2 or CN, at least one of
the group R 2 , R 3 , R 4 , and R 5 is not H, and if one
of the group R 2 , R 3 , R 4 and R 5 is CH 3 , at least
one of the remaining group is not H; and
35
(b) recovering the urea compound formed in step (a)
above.
WO 90/02112
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PCT/US89/03616
40* The process of claim 39 vherein R x is an optionally
substituted phenyl, optionally substituted pyridyl, or
optionally substituted pyrimidyl.
5
41. The process of claim 39 vherein R r is an optionally
substituted phenyl vherein X 2 , X 3 , X 5 and X 6 are H, and X 4
is selected from the group consisting of CN, NO,, C0,C H
2 2 2 5 ^
C0 2 CH 3 , C0NH 2 , CI, Br, F, I, HCO, CH 3 C0, S0 2 NH 2 and CH 3 S0 2 ,
10 and is 0. /
42. The process of claim 39 wherein R 3 , R 4 and R 5 are H and R,
is selected from the group consisting of phenyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, naphthyl, quinolyl, and (CH 2 ) 1 _ 6
15 cycloalkyl (C 3 -C 8 ).
43. The process of claim 39 wherein X 4 is selected from the
group consisting of CN, N0 2 , C0NH 2 , CH0, C0 2 CH 3 , and
20
C0 2 C2 H5 •
44, The process of claim 39 vherein R 2 is selected from the
.group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl .
25 45. The process of claim 39 vherein R t is an optionally
substituted pyridyl.
46. The process of claim 39 vherein R t is an optionally
substituted pyrimidyl.
30
47. The process of claim 39 vherein step (a) is carried out in
the presence of a base.
48. The process of claim 39 vherein step (a) is carried out in
35 the presence of a solvent.
WO 90/02112
-71-
PCT/US89/03616
1
49. The process of claim 48 wherein said solvent is acetoni trile
50. The process of claim 48 wherein said solvent is a mixture of
acetonitrile and water*
5
51. A sweet foodstuff including one or more compounds of Claim 1
as the sweetening agent.
52. An edible composition comprising
10 (a) a foodstuff; and
(b) one or more sweetening agents selected from the
group consisting of the compounds of Claim 1,
15 53. A process comprising
(a) reacting a compound of the formula
^iNH 2
20 with a compound of the formula
25
R-5
\ /
X,CN - C - C - C00R fi
R/t Re
wherein X x is 0 or S, wherein R x is an optionally substituted
cyclic, optionally substituted heterocyclic including
optionally substituted heteroaromatic, optionally
substituted bicyclic including optionally substituted
30 aromatic bicycliCj or optionally substituted phenyl f said
phenyl corresponding to:
<f^2
35 X 5 -^ %
wherein X 2 , X 3 , X 4 , X 5 and X 6 are the same or different and are
WO 90/02112
-72-
PCT/US89/03616
selected from the group consisting of:
H,
CF 3 ,
CF 2 CF 3 ,
Cj^-Ci alkyl,
CH=N0CH 3 ,
CI, with the proviso that X 3 and X 5 may not both
be CI,
10 Br,
I,
F,
CH=N0H ,
CHO,
15 CH 2 0CH 3 ,
CH 2 0H,
CN,
COCF3 ,
C0C 1 -C 3 alkyl,
20 C0NH 2 ,
CONHCj-Cs alkyl,
CONCC^-C, alkyl) 2 ,
C00C 1 -C 3 alkyl,
C00H ,
25 NH 2 ,
NHCi-Ca alkyl,
NCCi-Cs alkyl) 2 ,
NHCHO ,
NHC0CH 3 ,
30 NHCONH 2 ,
NHS0 2 CH 3 ,
Cj-Cj alkyl COOH,
N0 2 ,
OCi-Cs alkyl, with the proviso that X 4 may not be 0CH 2 CH 3
35 OCOCH 3 ,
OH,
WO 90/02112
-73-
PCT/US89/03616
SC 1 -C 3 alkyl,
SGC 1 -C 3 alkyl,
S0 2 C 1 -C 3 alkyl,
S0 2 NH 2 ,
5 S0 2 NHC 1 -C 3 alkyl,
S0 2 N(C 1 -C 3 alkyl) 2 ,
S0 3 H,
and where substituents at any two of X 2 , X 3 , X 4 , X 5 or X 6
form a fused ring,
10
wherein R 2 , R 3 , R 4 , and R 5 are the same or different and are
selected from the group consisting of
H,
optionally substituted straight chain or branched
15 Ci-Cio alkyl,
optionally substituted cyclic C z -C 10 alkyl, optionally
substituted cyclic,
optionally substituted heterocyclic including
optionally substituted heteroaromatics , optionally
20 substituted bicyclic including optionally substituted
aromatic bicyclic, or optionally substituted phenyl,
and enantiomers and physiologically acceptable salts
thereof with the proviso that if X 4 is N0 2 or CN, at
least one of the group R 2 , R 3 , R 4 , and R 5 is not H, and
25 if one of the group R 2 , R 3 , R 4 and R 5 is CH 3 , at least
one of the remaining groups is not H; and
and wherein R 6 is methyl, ethyl, propyl, or butyl, and
30 (b) hydrolyzing the resulting compound; and
(c) recovering the isolated desired urea compound or salt
thereof formed in step (a).
35 54. The edible composition of claim 53 further comprising a
sweetening agent selected from the group consisting of
-74-
PCT/US89/03616
sucrose, corn syrups, fructose, aspartame, alitame,
neohesperidin dihydrochalcone, high fructose corn syrup,
hydrogenated isomaltulose, stevioside type sweeteners,
L-sugars, lactitol, neosugar glycyrrhizin, xylitol,
acesulfam-K, sodium saccharin, potassium saccharin, calcium
saccharin, cyclamic acid and the sodium, potassium, and
calcium salts thereof, sucralose, monellin, thauroatin and
mixtures thereof.
The edible composition of claim 53 comprising a beverage-
The edible composition of claim 53 comprising a confecti
on
A composition for use in preparing the compositions of claim
1 corresponding to the formula
< /
H 2 N- C - C -COOH or salts thereof
R 4 R 5
wherein R 2 , R 3 , R 4 , and R 5 are the same or different and are
selected from the group consisting of
H,
optionally substituted cyclic C 3 -C 10 alkyl,
optionally substituted straight chain or branched
Ci-Ci,, alkyl
optionally substituted cyclic,
optionally substituted heterocyclic including
substituted heteroaromatics, optionally substituted
bicyclic including optionally substituted aromatic
bicyclic, or optionally substituted phenyl, and
enantiomers and physiologically acceptable salts
thereof vith the proviso that if X 4 is N0 2 , at least
one of the group R 2 , R 3 , R 4 , and R 5 is not H and if one
of the group R 2 , R 3 , R 4 and R 5 is CH 3 , at least one of
the remaining groups is not H.
WO 90/02112
PCT/US89/03616
-75-
58. A process for producing a first urea or thiourea of the
formula
1 2
\-^oy^ - c - n - \K-
H 2 NC0-^O>N - C - N - C - C - COOH and all salts thereof
H k R„ R,
4 "5
from a second urea or thiourea of the formula
X«i R-5 R<9
> v l( \/
NC-< 0> — N - C - N - C - C - COOH and all salts thereof
W I I /\
10 H H R^ R 5
wherein X^^ is 0 or S, and wherein
R 2 , R 3 , R 4 and R 5 are the same or different and
15 are selected from the group consisting of:
H
optionally substituted straight chain or branched
Ci-Cio alkyl,
optionally substituted cyclic C 3 -C 10 alkyl,
20 optionally substituted cyclic,
optionally substituted heterocyclic including optionally
substituted heteroaromatic, optionally
substituted bicyclic including optionally substituted
aromatic bicyclic, or optionally substituted phenyl,
25 and enantiomers and physiologically acceptable
salts thereof, said process
comprising the step of:
reacting said second urea or thiourea with alkaline hydrogen
peroxide to produce said first urea or thiourea.
30
59. A process for obtaining one isomer of a first compound of
the formula:
X4 R-3
r _ N - C - N - C - C - COOH and all salts thereof
35 H H R 4 R 5
WO 90/02112
-76-
PCT/US89/03616
10
15
wherein X± is 0 or S, Rj is
an optionally substituted cyclic, optionally substituted
heterocyclic including optionally substituted heteroaromatic,
optionally substituted bicyclic including optionally
substituted aromatic bicyclic, or optionally substituted
phenyl, said phenyl corresponding to:
wherein X 2 , X 3 , X 4 , X 5 and X s are the same or different and
are selected from the group consisting of
H,
CF 3 ,
CF 2 CF 3 ,
CH 2 CF 3 ,
20 C x -C 4 alkyl,
CH=N0CH 3 ,
CI, with the proviso that X 3 and X 5 may not both be CI,
Br,
I,
25 F,
CH=N0CH 3 ,
CH=N0H ,
CHO,
CH 2 0CH 3 ,
30 CH 2 0H,
CN,
C0CF 3 ,
C0C 1 -C 3 alkyl,
C0NH 2 ,
35 CONHCi-Ca alkyl,
CONCCi^ alkyl) 2 ,
WO 90/02112
-77-
PCT/US89/03616
000^-03 alkyl,
COOH,
NH 2 ,
NHCj-Cj alkyl,
5 IKC^-Cs alkyl) 2 ,
NHCHO ,
CI, with the proviso that X 3 and X 5 may not both
be CI,
Br,
10 I,
F,
NHCOCH3 ,
NHC0NH 2 ,
NHS0 2 CH 3 ,
15 Zi-Zi alkyl COOH,
N0 2 ,
#
OCi-Ca alkyl, with the proviso that X 4 may not be
0CH 2 CH 3
OCOCH3 ,
20 OH,
SC 1 -C 3 alkyl,
S0C 1 -C 3 alkyl,
S0 2 C 1 -C 3 alkyl,
S0 2 NH 2 ,
25 SO^H^-Cs alkyl,
SOjNCCi-Cs alkyl) 2
S0 3 H,
and where substituents at any two of X 2 , X 3 , X 4 ,
X 5 or X 6 form a fused ring,
30
R 2 and R 3 are the same or different and are selected from the
group consisting of
35
H,
optionally substituted straight chain or branched
Ci-Cio alky},
WO 90/02112
-78-
PCT/US89/03616
optionally substituted cyclic C 3 -C 10 alkyl, optionally
substituted cyclic,
optionally substituted heterocyclic, optionally substituted
bicyclic, or optionally substituted phenyl, and enantiomers
5 and physiologically acceptable salts thereof with the proviso
that if X 4 is N0 2 or CN, at least one of the group R 2 , R
R 4 , and R 5 is not H, and if one of the group R 2 , R 3 , r 4 and
R 5 is CH 3 , at least one of the remaining group is not H,
10 comprising the steps of:
reacting an aldehyde with an amine to produce
a Schiff base;
reacting said Schiff base with a methyl haloacetate and a
15 metal to produce a diastereomeric mixture of a ^-lactam;
hydrolyzing said P-lactam to produce a diastereomeric
mixture of a first <3-amino acid;
ester ifying said first g-amino acid;
isolating one isomer of the ester of said diastereomeric
20 mixture of said first £-amino acid;
hydrogenolyzing said ester to produce one stereoisomer of a
second 3-amino acid;
reacting said stereoisomer of the second amino acid with an
isocyanate or isothiocyanate to
25 produce said first compound*
60. The process of claim 59 wherein said metal is zinc.
30
61. The process of claim 59 wherein said second 3-amino acid is
produced by reaction of said first £-amino acid with
palladium and carbon.
35
WO 90/02112
-79-
PCT/US89/03616
20
62. A process for obtaining one isomer of a first compound of the
formula:
R^ R-a
II 1/
R x _ N-C-N-C-C- C00H and all salts thereof
H Rg
wherein X x is 0 or S, R x is
■
an optionally substituted cyclic, optionally substituted
10 heterocyclic including optionally substituted heteroaromatic,
optionally substituted bicyclic including optionally
substituted aromatic bicyclic, or optionally substituted
phenyl, said phenyl corresponding to:
15
wherein X 2 , X 3 , X 4 , X 5 and X 6 are the same or different and are
selected from the group consisting of
H,
CF 3 ,
CF 2 CF 3 ,
CF 3 ,
25 d-C 4 alkyl,
CH=N0CH3 ,
CH=N0CH 3 ,
CI, vith the proviso that X 3 and X 5 may not both be Cl,
Br,
30 I,
F,
CH=N0H ,
CH0,
CH 2 0CH 3 ,
35 CH 2 0H,
CN,
WO 90/02112
-80-
PCT/US89/03616
10
C0CF 3 ,
COCi-03 alkyl,
C0NH 2 ,
C0NHC 1 -C 3 alkyl,
CONCCi-^ alkyl) 2 ,
COOC^-C, alkyl,
C00H ,
NH 2 ,
NHCj -C 3 alkyl,
N^-C, alkyl) 2 ,
NHCHO,
NHC0CH 3 ,
NHCONH 2 ,
NHS0 2 CH 3 ,
15 Cj-Cs alkyl COOH,
N0 2 ,
0C t -C 3 alkyl, with the proviso that X 4 may not be
0CH 2 CH 3
OC0CH 3 ,
20 OH,
-C 3 alkyl,
SOCi-Ca alkyl,
SOjCi-Cs. alkyl,
S0 2 NH 2 ,
25 S0 2 NHC X -C 3 alkyl,
S0 2 N(C 1 -C 3 alkyl) 2 ,
S0 3 H,
and where substituents at any two of X,, X, X
X 5 or X 6 form a fused ring,
30
R 2 and R 3 are the same or different and are selected from the
group consisting of
H,
35 optionally substituted straight chain or branched
C t -C l0 alkyl,
WO 90/02112
-81-
PCT/US89/03616
optionally substituted cyclic C 3 -C 10 alkyl, optionally
substituted cyclic,
optionally substituted heterocyclic including
heteroaromatics, optionally substituted bicyclic including
5 optionally substituted aromatic bicyclic, or optionally
substituted phenyl, and enantiomers and physiologically
acceptable salts thereof with the proviso that if X 4 is N0 2
or CN, at least one of the group R 2 , R 3 , R 4 , and R 5 is not H,
and if one of the group R 2 , R 3 , R 4 and R 5 is CH 3 , at least
10 one of the remaining group is not H,
comprising the steps of:
reacting an aldehyde with an amine to produce a Schiff base;
reacting said Schiff base vith methyl haloacetate and a metal
to produce a diastereomeric mixture of a (3-lactam;
15 isolating one diastereomer of said 0-lactam;
hydrolyzing said isomer of said (5-lactam to produce one
stereoisomer of first g-amino acid;
hydrogenolyzing said stereoisomer of first (J-amino acid to
produce one stereoisomer of said second g-amino acid;
20 reacting said stereoisomer of said second g-amino acid with
an isocyanate or isothiocyanate to produce said first
compound*
25
0
30
35
INTERNATIONAL SEARCH REPORT
international Aooncano" N
I. CLASSIFICATION
iUBJECT MATTER Of sevgrai cMsstncation svmcois aooly. -
TCT/US89/036I6
,t? ail) 6
£j£?/?\ ng ^i^JT^JL'H"/ 3 , 1 ^ 316 " 1 Classification (IPC) or :o ootn National Classification and IPC
IPC(4): C07C 127/19; A23L 1/236
U.S.C1-: 558/413,414,415,416,417; 56 0/251; 562/426,428,430,439
U FIELDS SEARCHED
Minimum Oocumenration Searched 7
Classiftcatton Svsie m
Classification Svmoois
U.S.
558/413,414,415,416,417; 560/251; 562/426,428,430,439
Documentation Searched other than Minimum Documentation
to the Extent that such Documents are Included m the Fields Searched •
Chemical Abstract Structure Search (Online)
1966 - To Date
III. DOCUMENTS CONSIDERED TO BE RELEVANT •
Category
C.iation of Document, 11 with indication. wnere appropriate, ot the relevant oassages 12
Relevant to Ctaim No. * 3
A
X
Chemical Abstracts, Vol . 94, No. 23
Abstract 186 226x issued 8 June 1981,
(Columbus, Ohio, U.S.A.) Tinti et al .
"Studies on sweeteners requiring the
simultaneous presence of both nitrogen
dioxide/cyanide and carboxyl groups".
Chemical Abstracts , Vol 106, No. 25,
Abstract 214 377j issued 22 June 1987
(Columbus, Ohio, U.S.A.) Tsuchiya et al
"Amino acid derivatives as sweeteners".
The Merck Index, Tenth Edition published by
Merck and Co , Inc. Rahway, N.J. (1983)
page 1293, entry no. 8886.
Kpart )-
38, 51&52
1 (part )-38
51&52
Kpart )-3
6-13, 17
20.21-
30-38 51
and 5 2
* Special categories of cited documents: 10
"A" document defining the general state of the art -which is not
considered to be of particular relevance
"E** earlier document but published on or after the international
filing date
"L" document which may throw doubts on priority clatm(s) or
which is cited to establish the publication date of another
citation or otner special reason (as specified)
"O" document referring to an oral disclosure, use. exhibition or
other means
"P" document published prior to the international filing date but
later than the priority date claimed
"T" later document oublished after the international filing date
or priority date and not in conflict with the aooncation out
cited to understand the principle or theory underlying the
invention
"X" document of particular relevance: the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step
"Y" document of particular relevance; the claimed invention
cannot be considered to involve an inventive step when the
document is comoineo with one or more other sucn docu-
ments, such comoination being obvious to a person skilled
m the art.
"A" document member of the same patent family
IV. CERTIFICATION
Date of the Actual Completion of the International Search
I Date of Mailing of this International Search Report
10 OCT
1989
15DEC 1983
International Searching Authority
ISA/US
Signajare of Authorized Officer
ZTTTNA " ITORTHINGTON-DAVI S
Form PCTrtS*21 0(i
tnee0(Rev.1147)
PCT/US89/03616
Attachment sheet 1
GROUP II:
GROUP III:
GROUP IV :
GROUP V:
GROUP VI i
GROUP VII:
Claims I(part)-38, 51 and 52 , drawn to the
formula
C-COOH
'\
4 R 5
wherein R± represents cyclic heterocyclic,
heteroaromatic, bicyclic, aromatic bicyclic
and phenyl .
Claims 39 50 , drawn to a process of preparing
compounds of GROUP I.
Claims 53-56. drawn to a process of preparing
compounds of GROUP I.
Claim 57 drawn to a process of preparing
compounds of GROUP I .
Claim 58 drawn to a process of preparing urea
or thiourea compounds of GROUP I -
Claims 59-61 drawn to a process of preparing
an isomeric compound of GROUP I.
Claim 62 drawn to a process of preparing an
isomeric compound of GROUP I.
X X R 2
RX-N-C-N-C-
PCT/US89/03616
D etailed Reasons for Holding Lack of
Unity of Invent ion
There is a lack of a significant common structural
moiety in GROUP I wherein R 1 represents cyclic,
heterocyclic, heteroaromat ic , bicyclic, aromatic bicyclic
and phenyl to which the claimed utility (sweetening
agent) may be attributed.
Inventions I and (ll to VII) are related as process of
making and product made. The inventions are distinct if
either or both of the following can be shown: (1) that
the process as claimed can be used to make other and
materially different product or (2) that the product as
claimed can be made by another and materially different
process. In the instant case the product as claimed can
be made by a materially different process such as GROUPS
II to VII.
Accordingly, the requirement of the unity of invention
have been set forth which includes a single general
invent ive concept ,
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